The Concise Guide to Pharmacology 2013/14: G Protein-Coupled Receptors

Abstract

The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.12444/full.

G protein-coupled receptors are one of the seven major pharmacological targets into which the Guide is divided, with the others being G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets.

It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in previous Guides to Receptors and Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and the Guide to Receptors and Channels, providing a permanent, citable, point-in-time record that will survive database updates.

An introduction to G protein-coupled receptors

G protein-coupled receptors (GPCRs) are the largest class of membrane proteins in the human genome. The term “7TM receptor” is commonly used interchangeably with “GPCR”, although there are some receptors with seven transmembrane domains that do not signal through G proteins. GPCRs share a common architecture, each consisting of a single polypeptide with an extracellular N-terminus, an intracellular C-terminus and seven hydrophobic transmembrane domains (TM1-TM7) linked by three extracellular loops (ECL1-ECL3) and three intracellular loops (ICL1-ICL3). About 800 GPCRs have been identified in man, of which about half have sensory functions, mediating olfaction (∼400), taste (33), light perception (10) and pheromone signalling (5)(Mombaerts, 2004). The remaining ∼350 non-sensory GPCRs mediate intercellular signalling by ligands that range in size from small molecules to peptides to large proteins; they are the targets for the majority of drugs in clinical usage (Overington et al., 2006; Rask-Andersen et al., 2011), although only a minority of these receptors are exploited therapeutically. The first classification scheme to be proposed for GPCRs (Kolakowski, 1994) divided them, on the basis of sequence homology, into six classes. These classes and their prototype members were as follows: Class A (rhodopsin-like), Class B (secretin receptor family), Class C (metabotropic glutamate), Class D (fungal mating pheromone receptors), Class E (cyclic AMP receptors) and Class F (frizzled/smoothened). Of these, classes D and E are not found in vertebrates. An alternative classification scheme “GRAFS” (Schioth & Fredriksson, 2005) divides vertebrate GPCRs into five classes, overlapping with the A-F nomenclature, viz:

Glutamate family (class C), which includes metabotropic glutamate receptors, a calcium-sensing receptor and GABA_B receptors, as well as three taste type 1 receptors (Page 1468) and a family of pheromone receptors (V2 receptors) that are abundant in rodents but absent in man (Mombaerts, 2004).

Rhodopsin family (class A), which includes receptors for a wide variety of small molecules, neurotransmitters, peptides and hormones, together with olfactory receptors, visual pigments, taste type 2 receptors (Page 1469) and five pheromone receptors (V1 receptors).

Adhesion family GPCRs are phylogenetically related to class B receptors, from which they differ by possessing large extracellular N-termini that are autoproteolytically cleaved from their 7TM domains at a conserved “GPCR proteolysis site” (GPS) which lies within a much larger (∼320 residue) “GPCR autoproteolysis-inducing” (GAIN) domain, an evolutionarily ancient motif also found in polycystic kidney disease 1 (PKD1)-like proteins, which has been suggested to be both required and sufficient for autoproteolysis (Promel et al., 2013).

Frizzled family consists of 10 Frizzled proteins (FZD(1-10)) and Smoothened (SMO). The FZDs are activated by secreted lipoglycoproteins of the WNT family, whereas SMO is indirectly activated by the Hedgehog (HH) family of proteins acting on the transmembrane protein Patched (PTCH).

Secretin family, encoded by 15 genes in humans. The ligands for receptors in this family are polypeptide hormones of 27-141 amino-acid residues; nine of the mammalian receptors respond to ligands that are structurally related to one another (glucagon, glucagon-like peptides (GLP-1, GLP-2), glucose-dependent insulinotropic polypeptide (GIP), secretin, vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP) and growth-hormone-releasing hormone (GHRH)) (Harmar, 2001).

GPCR families

Family	Class A (Rhodopsin)	Class B (Secretin)	Class C (Glutamate)	Adhesion	Frizzled
Receptors with known ligands	197a	15	12	0	11
Orphans	87 (54)a	–	8 (1)a	26 (6)a	0
Sensory (olfaction)	390b,c	–	–	–	–
Sensory (vision)	10d opsins	–	–	–	–
Sensory (taste)	30c taste 2	–	3c taste 1	–	–
Sensory (pheromone)	5c vomeronasal 1	–	–	–	–
Total	719	15	22	33	11

^aNumbers in brackets refer to orphan receptors for which an endogenous ligand has been proposed in at least one publication, see Davenport et al. (2013)

^bOlender et al. (2008);

^cMombaerts (2004);

^dTerakita (2005).

Conflict of interest

The authors state that there is no conflict of interest to disclose.

List of records presented

1. 1462 Orphan GPCRs

2. 1471 5-Hydroxytryptamine receptors

3. 1474 Acetylcholine receptors (muscarinic)

4. 1476 Adenosine receptors

5. 1478 Adhesion Class GPCRs

6. 1480 Adrenoceptors

7. 1484 Angiotensin receptors

8. 1485 Apelin receptor

9. 1486 Bile acid receptor

10. 1487 Bombesin receptors

11. 1488 Bradykinin receptors

12. 1489 Calcitonin receptors

13. 1491 Calcium-sensing receptors

14. 1492 Cannabinoid receptors

15. 1494 Chemerin receptor

16. 1495 Chemokine receptors

17. 1500 Cholecystokinin receptors

18. 1501 Complement peptide receptors

19. 1502 Corticotropin-releasing factor receptors

20. 1503 Dopamine receptors

21. 1505 Endothelin receptors

22. 1506 Estrogen (G protein-coupled) receptor

23. 1507 Formylpeptide receptors

24. 1508 Free fatty acid receptors

25. 1510 Frizzled Class GPCRs

26. 1511 GABA_B receptors

27. 1513 Galanin receptors

28. 1514 Ghrelin receptor

29. 1515 Glucagon receptor family

30. 1517 Glycoprotein hormone receptors

31. 1518 Gonadotrophin-releasing hormone receptors

32. 1519 GPR18, GPR55 and GPR119

33. 1520 Histamine receptors

34. 1521 Hydroxycarboxylic acid receptors

35. 1522 Kisspeptin receptors

36. 1523 Leukotriene, lipoxin and oxoeicosanoid receptors

37. 1525 Lysophospholipid (LPA) receptors

38. 1526 Lysophospholipid (S1P) receptors

39. 1527 Melanin-concentrating hormone receptors

40. 1528 Melanocortin receptors

41. 1529 Melatonin receptors

42. 1530 Metabotropic glutamate receptors

43. 1532 Motilin receptor

44. 1533 Neuromedin U receptors

45. 1534 Neuropeptide FF/neuropeptide AF receptors

46. 1535 Neuropeptide S receptor

47. 1536 Neuropeptide W/neuropeptide B receptors

48. 1537 Neuropeptide Y receptors

49. 1538 Neurotensin receptors

50. 1539 Opioid receptors

51. 1541 Orexin receptors

52. 1542 Oxoglutarate receptor

53. 1543 P2Y receptors

54. 1545 Parathyroid hormone receptors

55. 1546 Peptide P518 receptor

56. 1547 Platelet-activating factor receptor

57. 1548 Prokineticin receptors

58. 1549 Prolactin-releasing peptide receptor

59. 1550 Prostanoid receptors

60. 1552 Proteinase-activated receptors

61. 1553 Relaxin family peptide receptors

62. 1555 Somatostatin receptors

63. 1556 Succinate receptor

64. 1557 Tachykinin receptors

65. 1558 Thyrotropin-releasing hormone receptors

66. 1559 Trace amine receptor

67. 1560 Urotensin receptor

68. 1561 Vasopressin and oxytocin receptors

69. 1562 VIP and PACAP receptors

Orphan GPCRs

Class A Orphans

Overview

Table 1 lists a number of putative GPCRs identified by IUPHAR 24, for which preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to a disease, or disorder. The GPCRs in Table 1 are all Class A, rhodopsin-like GPCRs. Class A orphan GPCRs not listed in Table 1 are putative GPCRs with as-yet unidentified endogenous ligands.

Table 1.

Class A orphan GPCRs with putative endogenous ligands

Nomenclature	HGNC, UniProt	Principal transduction	Endogenous agonists (pKi)	Radioligands (Kd)	Selective agonists (pKi)	Comment
GPR1	GPR1, P46091	–	chemerin (RARRES2, Q99969) (pKd 8.28) 2	–	–	Reported to act as a co-receptor for HIV 86.
GPR3	GPR3, P46089	Gs	–	–	–	sphingosine 1-phosphate was reported to be an endogenous agonist 97, but this finding was not replicated in subsequent studies 106. Reported to activate adenylyl cyclase constitutively through Gs 21. Gene disruption results in premature ovarian aging 55, reduced β-amyloid deposition 96 and hypersensitivity to thermal pain 81 in mice.
GPR4	GPR4, P46093	Gs	–	–	–	An initial report suggesting activation by lysophosphatidylcholine and sphingosylphosphorylcholine 111 has been retracted 112. GPR4, GPR65, GPR68 and GPR132 are now thought to function as protein-sensing receptors detecting acidic pH [17],[85]. Gene disruption is associated with increased perinatal mortality and impaired vascular proliferation 113.
GPR6	GPR6, P46095	Gs	–	–	–	An initial report that sphingosine 1-phosphate (S1P) was a high-affinity ligand (EC50 value of 39nM) [36],[97] was not repeated by β-arrestin PathHunter[TM] assays [90],[106]. Reported to activate adenylyl cyclase constitutively through Gs and to be located intracellularly 75. Gpr6-deficient mice showed reduced striatal cyclic AMP production in vitro and selected alterations in instrumental conditioning in vitro. 62.
GPR12	GPR12, P47775	–	–	–	–	Reports that sphingosine 1-phosphate was a ligand of GPR12 [35],[97] have not been replicated in β-arrestin-based assays [90],[106]. Gene disruption results in dyslipidemia and obesity 6.
GPR15	GPR15, P49685	–	–	–	–	Reported to act as a co-receptor for HIV 19. In an infection-induced colitis model, Gpr15 knockout mice were more prone to tissue damage and inflammatory cytokine expression 47.
GPR17	GPR17, Q13304	–	LTC4 (pEC50 7.83 – 9.48) 16, LTD4 (pEC50 8.14 – 8.36) 16, UDP-glucose (pEC50 5.92 – 9.52) [5],[16], UDP-galactose (pEC50 5.96 – 8.92) [5],[16], UDP (pEC50 5.97 – 8.8) [5],[16]	–	–	Reported to be a dual leukotriene and UDP receptor 16. Another group instead proposed that GPR17 functions as a negative regulator of the CysLT1 receptor response to leukotriene D4 (LTD4). For further discussion, see 17. Reported to antagonize CysLT1 receptor signalling in vivo and in vitro 65.
GPR20	GPR20, Q99678	–	–	–	–	Reported to inhibit adenylyl cyclase constitutively through Gi/o 30. GPR20 deficient mice exhibit hyperactivity characterised by increased total distance travelled in an open field test 8.
GPR22	GPR22, Q99680	Gi/o	–	–	–	Gene disruption results in increased severity of functional decompensation following aortic banding 1. Identified as a susceptibility locus for osteoarthritis [23],[46],[98].
GPR26	GPR26, Q8NDV2	Gs	–	–	–	Has been reported to activate adenylyl cyclase constitutively through Gs 40. Gpr26 knockout mice show increased levels of anxiety and depression-like behaviours 108.
GPR31	GPR31, O00270	–	12S-HETE (Selective) (pEC50 9.55 - Mouse) 27	–	–	–
GPR32	GPR32, O75388	Not yet established	resolvin D1 (Selective) (pEC50 11.06) 51, LXA4 (Selective) (pEC50 9.7) 51	[3H]resolvin D1 (Agonist) (2x10-10 M) 51	–	resolvin D1 (more potently than LxA4) has been demonstrated to activate GPR32 in two publications [15],[51]. The pairing was not replicated in a recent study based on β-arrestin recruitment 90. GPR32 is a pseudogene in mice and rats.
GPR34	GPR34, Q9UPC5	Gi/Go	lysophosphatidylserine (Selective) (pEC50 6.57 – 6.89) [48],[91]	–	–	Lysophosphatidylserine has been reported to be a ligand of GPR34 in several publications, but the pairing was not replicated in a recent study based on β-arrestin recruitment 90. Fails to respond to a variety of lipid-derived agents 106. Gene disruption results in an enhanced immune response 59.
GPR35	GPR35, Q9HC97	–	2-oleoyl-LPA (pEC50 7.3 – 7.52) 73, kynurenic acid (pEC50 3.9 – 4.41) [90],[99]	–	–	Several studies have shown that kynurenic acid is an agonist of GPR35 but it remains controversial whether the proposed endogenous ligand reaches sufficient tissue concentrations to activate the receptor 53. 2-oleoyl-LPA has also been proposed as an endogenous ligand 73 but these results were not replicated in in a recent β-arrestin assay 90. The phosphodiesterase inhibitor zaprinast 95 has become widely used as a surrogate agonist to investigate GPR35 pharmacology and signaliing 95. GPR35 is also activated by the pharmaceutical adjunct pamoic acid 110.
GPR37	GPR37, O15354	Gi/Go	–	–	neuropeptide head activator (pEC50 7.96 – 8.48) 78	Reported to associate and regulate the dopamine transporter 68 and to be a substrate for parkin 66. Gene disruption results in altered striatal signalling 67.
GPR39	GPR39, O43194	Gq/G11	Zn2+ 33	–	–	Zn2+ has been reported to be a potent and efficacious agonist of human, mouse and rat GPR39 105. obestatin (GHRL, Q9UBU3), a fragment from the ghrelin precursor, was reported initially as an endogenous ligand, but subsequent studies failed to reproduce these findings. Has been reported to be down-regulated in adipose tissue in obesity-related diabetes 10. Gene disruption results in obesity and altered adipocyte metabolism 77.
GPR50	GPR50, Q13585	–	–	–	–	GPR50 is structurally related to MT1 and MT2 melatonin receptors, with which it heterodimerises constitutively and specifically 57. GPR50 knockout mice display abnormal thermoregulation and are much more likely than wild-type mice to enter fasting-induced torpor 3.
GPR61	GPR61, Q9BZJ8	Gs	–	–	–	GPR61 deficient mice exhibit obesity associated with hyperphagia 70. Although no endogenous ligands have been identified, 5-(nonyloxy)tryptamine has been reported to be a low affinity inverse agonist 94.
GPR63	GPR63, Q9BZJ6	–	–	–	–	sphingosine 1-phosphate and dioleoylphosphatidic acid have been reported to be low affinity agonists for GPR63 72 but this finding was not replicated in a β-arrestin-based assay 106.
GPR65	GPR65, Q8IYL9	Gs	–	–	–	GPR4, GPR65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [17],[85]. Reported to activate adenylyl cyclase; gene disruption leads to reduced eosinophlia in models of allergic airway disease 50.
GPR68	GPR68, Q15743	–	–	–	–	Gpr68 was previously identified as a receptor for sphingosylphosphorylcholine (SPC) 103, but the original publication has been retracted 104. GPR4, GPR65, GPR68 and GPR132 are now thought to function as protein-sensing receptors detecting acidic pH [17],[85]. A family of 3,5-disubstituted isoxazoles were identified as agonists of GPR68 82.
GPR75	GPR75, O95800	Gq/G11	–	–	–	CCL5 (CCL5, P13501) was reported to be an agonist of GPR75 37, but the pairing could not be repeated in a recent β-arrestin assay 90.
GPR84	GPR84, Q9NQS5	Gi/Go	–	–	decanoic acid (pEC50 5.0 – 5.4) [90],[100], undecanoic acid (pEC50 5.1) 100, lauric acid (pEC50 5.05) 100	Medium chain free fatty acids with carbon chain lengths of 9-14 activate GPR84 [92],[100]. A surrogate ligand for GPR84, 6-n-octylaminouracil has also been proposed 92.
GPR87	GPR87, Q9BY21	–	LPA (pEC50 7.44) [69],[93]	–	–	–
GPR88	GPR88, Q9GZN0	–	–	–	–	Gene disruption results in altered striatal signalling 63.
GPR132	GPR132, Q9UNW8	Gs	–	–	–	GPR4, GPR65, GPR68 and GPR132 are now thought to function as protein-sensing receptors detecting acidic pH [17],[85]. Reported to respond to lysophosphatidylcholine 41, but later retracted 102.
GPR149	GPR149, Q86SP6	–	–	–	–	Gpr149 knockout mice displayed increased fertility and enhanced ovulation, with increased levels of FSH receptor and cyclin D2 mRNA levels 20.
GPR183	GPR183, P32249	–	7α,25-dihydroxycholesterol (Selective) (pEC50 8.1 – 9.85) [28],[60], 7α,27-dihydroxycholesterol (Selective) (pEC50 8.89) 60, 7β, 25-dihydroxycholesterol (Selective) (pEC50 8.68) 60, 7β, 27-dihydroxycholesterol (Selective) (pEC50 7.29) 60	–	–	Two independent publications have shown that 7α,25-dihydroxycholesterol is an agonist of GPR183 and have demonstrated by mass spectrometry that this oxysterol is present endogenously in tissues [28],[60]. Gpr183-deficient mice show reduction in the early antibody response to a T-dependent antigen. GPR183-deficient B cells fail to migrate to the outer follicle and instead stay in the follicle centre [44],[76].
LGR4	LGR4, Q9BXB1	–	R-spondin-2 (RSPO2, Q6UXX9) (Selective) (pEC50 12.52) 9, R-spondin-1 (RSPO1, Q2MKA7) (Selective) (pEC50 10.7) 9, R-spondin-3 (RSPO3, Q9BXY4) (Selective) (pEC50 10.7) 9, R-spondin-4 (RSPO4, Q2I0M5) (Selective) (pEC50 10.05) 9	–	R-spondin-2 (RSPO2, Q6UXX9) (Selective) (pEC50 12.52) 9, R-spondin-1 (RSPO1, Q2MKA7) (Selective) (pEC50 10.7) 9, R-spondin-3 (RSPO3, Q9BXY4) (Selective) (pEC50 10.7) 9, R-spondin-4 (RSPO4, Q2I0M5) (Selective) (pEC50 10.05) 9	LGR4 does not couple to heterotrimeric G proteins or to β-arrestin when stimulated by the R-spondins, indicating a unique mechanism of action. R-spondins bind to LGR4, which specifically associates with Frizzled and LRPs—proteins that are activated by the extracellular Wnt molecules and then trigger canonical Wnt signalling to increase gene expression [9],[18],[80]. Gene disruption leads to multiple developmental disorders [39],[64],[89],[101].
LGR5	LGR5, O75473	–	R-spondin-2 (RSPO2, Q6UXX9) (Selective) (pEC50 12.0) 9, R-spondin-1 (RSPO1, Q2MKA7) (Selective) (pEC50 11.1) 9, R-spondin-3 (RSPO3, Q9BXY4) (Selective) (pEC50 11.0) 9, R-spondin-4 (RSPO4, Q2I0M5) (Selective) (pEC50 9.4) 9	–	R-spondin-2 (RSPO2, Q6UXX9) (Selective) (pEC50 12.0) 9, R-spondin-1 (RSPO1, Q2MKA7) (Selective) (pEC50 11.1) 9, R-spondin-3 (RSPO3, Q9BXY4) (Selective) (pEC50 11.0) 9, R-spondin-4 (RSPO4, Q2I0M5) (Selective) (pEC50 9.4) 9	The four R-spondins can bind to LGR4, LGR5, and LGR6, which specifically associate with Frizzled and LRPs—proteins that are activated by extracellular Wnt molecules- and then trigger canonical Wnt signalling to increase gene expression [9],[18].
LGR6	LGR6, Q9HBX8	–	R-spondin-1 (RSPO1, Q2MKA7) (Selective) [9],[18], R-spondin-2 (RSPO2, Q6UXX9) (Selective) [9],[18], R-spondin-3 (RSPO3, Q9BXY4) (Selective) [9],[18], R-spondin-4 (RSPO4, Q2I0M5) (Selective) [9],[18]	–	–	–
MAS1	MAS1, P04201	Gq/G11	angiotensin-(1-7) (AGT, P01019) (Selective) 84	–	–	–
MRGPRD	MRGPRD, Q8TDS7	Gi/Go	β-alanine (pEC50 4.8) [87],[90]	–	–	An endogenous peptide with a high degree of sequence similarity to angiotensin-(1-7) (AGT, P01019), alamandine, was shown to promote NO release in MrgD-transfected cells. The binding of alamandine to MRGPRD to was shown to be blocked by D-Pro7-angiotensin-(1–7), β-alanine and PD123319 54. Genetic ablation of MRGPRD+ neurons of adult mice decreased behavioural sensitivity to mechanical stimuli but not to thermal stimuli 11.
MRGPRX1	MRGPRX1, Q96LB2	Gq/G11	BAM8-22 (PENK, P01210) (Selective) (pEC50 5.3 – 7.8) [13],[56],[90]	–	–	Reported to mediate the sensation of itch [61],[88]. Reports that BAM8-22 (PENK, P01210) was the most potent of a series of proenkephalin A–derived peptides as an agonist of MRGPRX1 in assays of calcium mobilisation and radioligand binding 56 were replicated in an independent study using a β-arrestin recruitment assay 90.
MRGPRX2	MRGPRX2, Q96LB1	–	PAMP-20 (ADM, P35318) (Selective) 42	–	PAMP-12 (human) (pEC50 7.24 – 7.68) 42, CST-14 {Sp: Mouse, Rat} (pEC50 6.9 – 7.6) [42],[79],[90]	A diverse range of substances has been reported to be agonists of MRGPRX2, with cortistatin 14 the highest potency agonist in assays of calcium mobilisation 79, also confirmed in an independent study using a β-arrestin recruitment assay 90.
P2RY10	P2RY10, O00398	–	sphingosine 1-phosphate (Selective) (pEC50 7.3) 69, LPA (Selective) (pEC50 6.9) 69	–	–	–
TAAR2	TAAR2, Q9P1P5	Gs	–	–	–	β-phenylethylamine > tryptamine 7 probable pseudogene in 10–15% of Asians due to a polymorphism (rs8192646) producing a premature stop codon at amino acid 168 17 see Page 139.

In addition the orphan receptors GPR18, GPR55 and GPR119 which are reported to respond to endogenous agents analogous to the endogenous cannabinoid ligands have been grouped together (see page 1519).

Table 2.

Class A Orphan GPCR with limited pharmacological or phenotypic profiles

Nomenclature	HGNC, UniProt	Principal transduction	Comment
GPR19	GPR19, Q15760	–	–
GPR21	GPR21, Q99679	Gq/11	Gpr21 knockout mice were resistant to diet-induced obesity, exhibiting an increase in glucose tolerance and insulin sensitivity and a modest lean phenotype 74.
GPR25	GPR25, O00155	–	–
GPR27	GPR27, Q9NS67	Gq/G11	Knockdown of Gpr27 reduces endogenous mouse insulin promotor activity and glucose stimulated insulin secretion 52.
GPR33	GPR33, Q49SQ1	Gi/Go	GPR33 is a pseudogene in most individuals, containing a premature stop codon within the coding sequence of the second intracellular loop 83.
GPR37L1	GPR37L1, O60883	Gi/Go	–
GPR45	GPR45, Q9Y5Y3	–	–
GPR52	GPR52, Q9Y2T5	–	–
GPR62	GPR62, Q9BZJ7	–	–
GPR78	GPR78, Q96P69	Gs	GPR78 has been reported to be constitutively active, coupled to elevated cAMP production 40.
GPR82	GPR82, Q96P67	–	Mice with Gpr82 knockout have a lower body weight and body fat content associated with reduced food intake, decreased serum triglyceride levels, higher insulin sensitivity and glucose tolerance 22.
GPR83	GPR83, Q9NYM4	–	One isoform has been implicated in the induction of CD4(+)CD25(+) regulatory T cells (Tregs) during inflammatory immune responses 29.
GPR85	GPR85, P60893	–	Proposed to regulate of hippocampal adult neurogenesis and neurogenesis-dependent learning and memory 14.
GPR135	GPR135, Q8IZ08	–	–
GPR139	GPR139, Q6DWJ6	Gq/G11	–
GPR141	GPR141, Q7Z602	–	–
GPR142	GPR142, Q7Z601	–	–
GPR146	GPR146, Q96CH1	–	Yosten et al. demonstrated inhibition of proinsulin C-peptide (INS, P01308)-induced stimulation of cFos expression folllowing knockdown of GPR146 in KATOIII cells, suggesting proinsulin C-peptide as an endogenous ligand of the receptor 107.
GPR148	GPR148, Q8TDV2	–	–
GPR150	GPR150, Q8NGU9	–	–
GPR151	GPR151, Q8TDV0	–	GPR151 responded to galanin with an EC50 value of 2 μM, suggesting that the endogenous ligand shares structural features with galanin (GAL, P22466) 34.
GPR152	GPR152, Q8TDT2	–	–
GPR153	GPR153, Q6NV75	–	–
GPR160	GPR160, Q9UJ42	–	–
GPR162	GPR162, Q16538	–	–
GPR171	GPR171, O14626	–	GPR171 has been shown to be activated by endogenous peptide BigLEN. This receptor-peptide interaction is believed to be involved in regulating feeding and metabolism responses 26.
GPR173	GPR173, Q9NS66	–	–
GPR174	GPR174, Q9BXC1	Gs	Reported to respond to lysophosphatidylserine (pEC50 7.1) 38.
GPR176	GPR176, Q14439	–	–
GPR182	GPR182, O15218	–	Rat GPR182 was first proposed as adrenomedullin receptor 43. However, it was later reported that rat and human GPR182 did not respond to adrenomedullin 45 and GPR182 is not currently considered to be a genuine adrenomedullin receptor 31.
MAS1L	MAS1L, P35410	–	–
MRGPRX3	MRGPRX3, Q96LB0	Gq/G11	–
MRGPRX4	MRGPRX4, Q96LA9	Gq/G11	–
MRGPRE	MRGPRE, Q86SM8	–	–
MRGPRF	MRGPRF, Q96AM1	–	MRGPRF has been reported to respond to stimulation by angiotensin metabolites 25.
MRGPRG	MRGPRG, Q86SM5	–	–
OPN3	OPN3, Q9H1Y3	–	–
OPN5	OPN5, Q6U736	Gi/Go	Evidence indicates OPN5 triggers a UV-sensitive Gi-mediated signalling pathway in mammalian tissues 49.
P2RY8	P2RY8, Q86VZ1	–	–

Table 3.

Class C Orphans

Nomenclature	HGNC, UniProt
GPR156	GPR156, Q8NFN8
GPR158	GPR158, Q5T848
GPR179	GPR179, Q6PRD1
GPRC5A	GPRC5A, Q8NFJ5
GPRC5B	GPRC5B, Q9NZH0
GPRC5C	GPRC5C, Q9NQ84
GPRC5D	GPRC5D, Q9NZD1

Taste 1 receptors

Overview

Whilst the taste of acid and salty foods appear to be sensed by regulation of ion channel activity, bitter, sweet and umami tastes are sensed by specialised GPCR. Two classes of taste GPCR have been identified, T1R and T2R, which are similar in sequence and structure to Class C and Class A GPCR, respectively. Activation of taste receptors appears to involve gustducin- (Gαt3) and Gα14-mediated signalling, although the precise mechanisms remain obscure. Gene disruption studies suggest the involvement of PLCβ2 109, TRPM5 109 and IP3 32 receptors in post-receptor signalling of taste receptors. Although predominantly associated with the oral cavity, taste receptors are also located elsewhere, including further down the gastrointestinal system, in the lungs and in the brain.

Sweet/Umami

T1R3 acts as an obligate partner in T1R1/T1R3 and T1R2/T1R3 heterodimers, which sense umami or sweet, respectively. T1R1/T1R3 heterodimers respond to L-glutamic acid and may be positively allosterically modulated by 5′-nucleoside monophosphates, such as 5'-GMP 58. T1R2/T1R3 heterodimers respond to sugars, such as sucrose, and artificial sweeteners, such as saccharin 71.

Nomenclature	TAS1R1	TAS1R2	TAS1R3
HGNC, UniProt	TAS1R1, Q7RTX1	TAS1R2, Q8TE23	TAS1R3, Q7RTX0
Principal transduction	–	–	–

Taste 2 receptors

Overview

Whilst the taste of acid and salty foods appear to be sensed by regulation of ion channel activity, bitter, sweet and umami tastes are sensed by specialised GPCR. Two classes of taste GPCR have been identified, T1R and T2R, which are similar in sequence and structure to Class C and Class A GPCR, respectively. Activation of taste receptors appears to involve gustducin- (Gαt3) and Gα14-mediated signalling, although the precise mechanisms remain obscure. Gene disruption studies suggest the involvement of PLCβ2 109, TRPM5 109 and IP3 32 receptors in post-receptor signalling of taste receptors. Although predominantly associated with the oral cavity, taste receptors are also located elsewhere, including further down the gastrointestinal system, in the lungs and in the brain.

Bitter

The composition and stoichiometry of bitter taste receptors is not yet established. Bitter receptors appear to separate into two groups, with very restricted ligand specificity or much broader responsiveness. For example, T2R5 responded to cycloheximide, but not 10 other bitter compounds 12, while T2R14 responded to at least eight different bitter tastants, including (-)-α-thujone and picrotoxinin 4.

Nomenclature	HGNC, UniProt
TAS2R1	TAS2R1, Q9NYW7
TAS2R3	TAS2R3, Q9NYW6
TAS2R4	TAS2R4, Q9NYW5
TAS2R5	TAS2R5, Q9NYW4
TAS2R7	TAS2R7, Q9NYW3
TAS2R8	TAS2R8, Q9NYW2
TAS2R8	TAS2R8, Q9NYW2
TAS2R9	TAS2R9, Q9NYW1
TAS2R10	TAS2R10, Q9NYW0
TAS2R13	TAS2R13, Q9NYV9
TAS2R14	TAS2R14, Q9NYV8
TAS2R16	TAS2R16, Q9NYV7
TAS2R19	TAS2R19, P59542
TAS2R20	TAS2R20, P59543
TAS2R42	TAS2R42, Q7RTR8
TAS2R30	TAS2R30, P59541
TAS2R31	TAS2R31, P59538
TAS2R39	TAS2R39, P59534
TAS2R40	TAS2R40, P59535
TAS2R50	TAS2R50, P59544
TAS2R43	TAS2R43, P59537
TAS2R46	TAS2R46, P59540
TAS2R41	TAS2R41, P59536
TAS2R60	TAS2R60, P59551
TAS2R38	TAS2R38, P59533

Other 7TM proteins

Nomenclature	HGNC, UniProt	Comment
GPR157	GPR157, Q5UAW9	GPR157 has ambiguous sequence similarities to several different GPCR families (class A, class B and the slime mould cyclic AMP receptor). Because of its distant relationship to other GPCRs, it cannot be readily classified.

5-Hydroxytryptamine receptors

Overview

5-HT receptors [nomenclature as agreed by NC-IUPHAR Subcommittee on 5-HT receptors 158 and subsequently revised 153 ] are, with the exception of the ionotropic 5-HT₃ class, GPCR receptors where the endogenous agonist is 5-HT. The diversity of metabotropic 5-HT receptors is increased by alternative splicing that produces isoforms of the 5-HT_2A (non-functional), 5-HT_2C (non-functional), 5-HT₄, 5-HT₆ (non-functional) and 5-HT₇ receptors. Unique amongst the GPCRs, RNA editing produces 5-HT_2C receptor isoforms that differ in function, such as efficiency and specificity of coupling to G_q/11 and also pharmacology 124,216. Most 5-HT receptors (except 5-ht_1e and 5-ht_5a/5b) play specific roles mediating functional responses in different tissues (reviewed by 197,211.

Nomenclature	5-HT1A receptor	5-HT1B receptor	5-HT1D receptor	5-ht1e receptor	5-HT1F receptor
HGNC, UniProt	HTR1A, P08908	HTR1B, P28222	HTR1D, P28221	HTR1E, P28566	HTR1F, P30939
Principal transduction	Gi/o	Gi/o	Gi/o	Gi/o	Gi/o
Selective agonists (pKi)	U92016A (9.7) 178, 8-OH-DPAT (8.4 – 9.4) 140,151,170,183,189,191,192, F15599 (8.6) 190	L-694,247 (9.2) 149, CP94253 (8.7) 167, eletriptan (8.0) 184, sumatriptan (Partial agonist) (6.5 – 8.1) 149,172,183,184,187,194,215	PNU109291 (9.1 - Gorilla) 143, L-694,247 (9.0) 217, eletriptan (8.9) 184, sumatriptan (8.0 – 8.7) 150,172,183,184,215	BRL-54443 (8.7) 136	BRL-54443 (8.9) 136, LY334370 (8.7) 213, LY573144 (8.7) 186, LY344864 (8.2) 195, eletriptan (8.0) 184, sumatriptan (7.2 – 7.9) 114,115,184,213
Selective antagonists (pKi)	NAD 299 (9.2) 161, WAY-100635 (7.9 – 9.2) 189,191, (S)-UH 301 (7.9) 189	GR-55562 (pKB 7.4) 159, SB 224289 (Inverse agonist) (8.2 – 8.6) 146,187,203, SB236057 (Inverse agonist) (8.2) 182	SB 714786 (9.1) 214, BRL-15572 (7.9) 196	–	–
Radioligands (Kd)	p-[18F]MPPF, [11C]WAY100635 (Antagonist), [3H]NAD 299 (Antagonist) (1.58x10-10 M) 160, [3H]WAY100635 (Antagonist) (3x10-10 M) 164, [3H]F13640 (Agonist, Full agonist) (1.4x10-9 M) 155, [3H]8-OH-DPAT (Agonist, Full agonist) (3.98x10-10 – 1x10-6 M) 122,162,188,191	[11C]AZ10419369, [3H]N-methyl-AZ10419369 (Antagonist) (3.7x10-10 M) 175, [125I]GTI (Agonist) (1.3x10-9 M - Rat) 130, [3H]GR 125,743 (Antagonist) (2.6x10-9 – 7.1x10-10 M) 149,218, [3H]alniditan (Agonist, Full agonist) (1x10-9 – 2.51x10-9 M) 171, [3H]eletriptan (Agonist, Partial agonist) (3x10-9 M) 184, [3H]sumatriptan (Agonist, Partial agonist) (1.1x10-8 M) 184	[3H]eletriptan (Agonist, Full agonist) (9x10-10 M) 184, [125I]GTI (Agonist) (1.3x10-9 M - Rat) 130, [3H]alniditan (Agonist, Full agonist) (1.2x10-9 – 1.4x10-9 M) 171, [3H]GR 125,743 (Antagonist) (2.8x10-9 M) 218, [3H]sumatriptan (Agonist, Full agonist) (7x10-9 M) 184	[3H]5-HT (Agonist, Full agonist) (6.31x10-9 – 7.94x10-9 M) 177,194	[3H]LY334370 (Agonist, Full agonist) (3.98x10-10 M) 213, [125I]LSD (Agonist) (9.8x10-10 M - Mouse) 116

Nomenclature	5-HT2A receptor	5-HT2B receptor	5-HT2C receptor
HGNC, UniProt	HTR2A, P28223	HTR2B, P41595	HTR2C, P28335
Principal transduction	Gq/11	Gq/11	Gq/11
Selective agonists (pKi)	DOI (7.4 – 9.2) 131,185,205	Ro 60-0175 (8.3) 166, BW723C86 (7.3 – 8.6) 119,166,201, DOI (7.6 – 7.7) 169,185,201,	Ro 60-0175 (7.7 – 8.2) 165,166, DOI (7.2 – 8.6) 142,185,201, lorcaserin (7.8) 209, WAY-163909 (6.7 – 8.0) 141
Selective antagonists (pKi)	ketanserin (8.1 – 9.7) 137,166,198, MDL-100,907 (pIC50 6.5 – 9.3) 166,173,199	RS-127445 (9.0 – 9.5) 128,166, EGIS-7625 (9.0) 168	FR260010 (9.0) 152, SB 242084 (8.2 – 9.0) 163,166, RS-102221 (8.3 – 8.4) 129,166
Radioligands (Kd)	[11C]MDL100907, [18F]altanserin (Antagonist), [3H]RP62203 (Antagonist) (1.3x10-10 M - Rat) 176, [3H]ketanserin (Antagonist) (2x10-10 – 2.9x10-9 M) 166,198	[3H]LSD (Agonist, Full agonist) (2.1x10-9 M) 198, [3H]mesulergine (5x10-9 – 1x10-8 M), [3H]5-HT (Agonist, Full agonist) (8x10-9 M - Rat) 212, [125I]DOI (2x10-8 – 2.5x10-8 M)	[3H]LSD (Agonist), [3H]mesulergine (Antagonist, Inverse agonist) (5x10-10 – 2.2x10-9 M) 144,198, [125I]DOI (6x10-9 – 2.5x10-8 M)

Nomenclature	5-HT4 receptor	5-ht5a receptor	5-ht5b receptor	5-HT6 receptor	5-HT7 receptor
HGNC, UniProt	HTR4, Q13639	HTR5A, P47898	HTR5BP, P31387	HTR6, P50406	HTR7, P34969
Principal transduction	Gs	Gi/Go	None identified	Gs	Gs
Selective agonists (pKi)	ML 10302 (Partial agonist) (7.9 – 9.0) 121,123,179–181, BIMU 8 (7.3) 138, RS67506 (pEC50 8.8 - Rat) 154	–	–	E-6801 (Partial agonist) (8.7) 157, WAY-181187 (8.7) 202	E55888 (8.6) 132
Selective antagonists (pKi)	RS 100235 (8.7 – 12.2) 138,200, SB 204070 (9.8 – 10.4) 120,179,180,210, GR 113808 (9.3 – 10.3) 117,120,123,138,180,200,210	SB 699551 (8.2) 139	–	SB399885 (9.0) 156, SB 271046 (8.9) 133, SB357134 (8.5) 134, Ro 63-0563 (7.9 – 8.4) 126,204	SB269970 (8.6 – 8.9) 207, SB656104 (8.7) 145, SB 258719 (Inverse agonist) (7.5) 208
Radioligands (Kd)	[123I]SB 207710 (8.6x10-11 M - Pig) 135, [3H]GR 113808 (Antagonist) (5x10-11 – 2x10-10 M) 117,120,181,210, [3H]RS 57639 (Agonist) (2x10-10 M - Guinea pig) 127, [11C]SB207145 (Antagonist) (2.8x10-9 M) 174	[125I]LSD (Agonist, Full agonist) (2x10-10 M) 148, [3H]5-CT (Agonist, Full agonist) (2.5x10-9 M) 148	[125I]LSD, [3H]5-CT	[3H]5-CT (Agonist), [125I]SB258585 (Antagonist) (1x10-9 M) 156, [3H]LSD (Agonist, Full agonist) (2x10-9 M) 125, [3H]Ro 63-0563 (Antagonist) (5x10-9 M) 126	[3H]5-CT (Agonist) (4x10-10 M) 207, [3H]SB269970 (Antagonist) (1.2x10-9 M) 207, [3H]5-HT (Agonist, Full agonist) (1x10-9 – 7.94x10-9 M) 118,206, [3H]LSD (Agonist, Full agonist) (2.51x10-9 – 3.16x10-9 M) 206

Comments

Tabulated pK_i and K_D values refer to binding to human 5-HT receptors unless indicated otherwise. Unreferenced values are extracted from the NC-IUPHAR database (www.iuphar-db.org). The nomenclature of 5-HT_1B/5-HT_1D receptors has been revised 153. Only the non-rodent form of the receptor was previously called 5-HT_1D;: the human 5-HT_1B receptor (tabulated) displays a different pharmacology to the rodent forms of the receptor due to Thr335 of the human sequence being replaced by Asn in rodent receptors. NAS181 is a selective antagonist of the rodent 5-HT_1B receptor. fananserin and ketanserin bind with high affinity to dopamine D4 and histamine H₁ receptors respectively, and ketanserin is a potent α1 adrenoceptor antagonist, in addition to blocking 5-HT_2A receptors. The human 5-ht_5A receptor has been claimed to couple to several signal transduction pathways when stably expressed in C6 glioma cells 193. The human orthologue of the mouse 5-ht_5b receptor is non-functional due to interruption of the gene by stop codons. The 5-ht_1e receptor appears not to have been cloned from mouse, or rat, impeding definition of its function. In addition to the receptors listed in the table, an 'orphan' receptor, unofficially termed 5-HT_1P, has been described 147.

Acetylcholine receptors (muscarinic)

Overview

Muscarinic acetylcholine receptors (nomenclature as agreed by NC-IUPHAR sub-committee on Muscarinic Acetylcholine Receptors, 224) are GPCR of the Class A, rhodopsin-like family where the endogenous agonist is acetylcholine. In addition to the agents listed in the table, AC-42, its structural analogues AC-260584 and 77-LH-28-1, N-desmethylclozapine, TBPB and LuAE51090 have been described as functionally selective agonists of the M₁ receptor subtype via binding in a mode distinct from that utilized by non-selective agonists 220,235,237,238,246,253,256,257,259. There are two pharmacologically characterised allosteric sites on muscarinic receptors, one defined by it binding gallamine, strychnine and brucine, and the other binds KT 5720, WIN 62,577, WIN 51,708 and staurosporine 240,241.

Nomenclature	M1 receptor	M2 receptor	M3 receptor	M4 receptor	M5 receptor
HGNC, UniProt	CHRM1, P11229	CHRM2, P08172	CHRM3, P20309	CHRM4, P08173	CHRM5, P08912
Principal transduction	Gq/11	Gi/o	Gq/11	Gi/o	Gq/11
Selective antagonists (pKi)	MT7 (11.0–11.1) 249, VU0255035 (7.8) 254	–	–	MT3 (8.7) 234,250	–
Selective allosteric regulators	BQCA (Positive) 244, brucine (Positive) 221, KT 5720 (Positive) 221, ML169 (Positive) 252, VU0029767 (Positive) 245, VU0090157 (Positive) 245	–	N-chloromethyl-brucine (Positive) 221, WIN 62,577 (Positive) 221	LY2033298 (Positive) 226, thiochrome (Positive) 221, VU0152099 (Positive) 222, VU0152100 (Positive) 222	VU0238429 (Positive) 223
Radioligands (Kd)	[11C]butylthio-TZTP, [11C]xanomeline, [18F](R,R)-quinuclidinyl-4-fluoromethyl-benzilate, [3H]QNB (Antagonist) (1.58×10−11–2.51×10−11 M) 229,251, [3H]N-methyl scopolamine (Antagonist) (5.01×10−11–1.58×10−9 M) 225,228–230,232–234,236,239, [3H]pirenzepine (Antagonist) (1.4×10−8 M) 263	[18F]FP-TZTP, [3H]QNB (Antagonist) (2.51×10−11–7.94×10−11 M) 251, [3H]N-methyl scopolamine (Antagonist) (1.25×10−10–5.01×10−7 M) 225,227,230,232–234,236,239,262	[3H]QNB (Antagonist) (3.98×10−11 M) 251, [3H]darifenacin (Antagonist) (3.16×10−10 M) 255, [3H]N-methyl scopolamine (Antagonist) (3.98×10−11–2.51×10−9 M) 225,227,230–232,234,236,239	[3H]QNB (Antagonist) (3.16×10−11–2×10−10 M) 229,251, [3H]N-methyl scopolamine (Antagonist) (6.3×10−11–1.58×10−8 M) 225,227,229,230,232,234,236,239,250,262	[3H]QNB (2×10−11–6×10−11 M), [3H]N-methyl scopolamine (Antagonist) (2×10−10–7.94×10−9 M) 225,227,230,234,236,262

Comments

LY2033298 and BQCA have also been shown to directly activate the M₄ and M₁ receptors, respectively, via an allosteric site 242,243,247,248. The allosteric site for gallamine and strychnine on M₂ receptors can be labelled by [3H]dimethyl-W84 260. McN-A-343 is a functionally selective partial agonist that appears to interact in a bitopic mode with both the orthosteric and an allosteric site on the M₂ muscarinic receptor 261. THRX-160209, hybrid 1 and hybrid 2, are multivalent (bitopic) ligands that also achieve selectivity for M₂ receptors by binding both to the orthosteric and a nearby allosteric site 219,258.

Although numerous ligands for muscarinic acetylcholine receptors have been described, relatively few selective antagonists have been described, so it is common to assess the rank order of affinity of a number of antagonists of limited selectivity (e.g. 4-DAMP, darifenacin, pirenzepine) in order to identify the involvement of particular subtypes.

Adenosine receptors

Overview

Adenosine receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Adenosine Receptors; 280) are activated by the endogenous ligand adenosine (potentially inosine also at A₃ receptors). Crystal structures for the antagonist-bound and agonist-bound A_2A adenosine receptors have been described 287,323.

Nomenclature	A1 receptor	A2A receptor	A2B receptor	A3 receptor
HGNC, UniProt	ADORA1, P30542	ADORA2A, P29274	ADORA2B, P29275	ADORA3, P33765
Principal transduction	Gi/o	Gs	Gs	Gi/o
(Sub)family-selective agonists (pKi)	NECA (5.3 – 8.2) 283,295,311,317,324	NECA (6.9 – 8.7) 270,276,283,299,303,324	NECA (5.7 – 6.9) 268,270,292,306,314,319,324	NECA (7.5 – 8.4) 270,283,289,312,320,324
Selective agonists (pKi)	5-Cl-5-deoxy-(±)-ENBA (9.29) 279, GR79236 (8.51 - Rat) 288, cyclopentyladenosine (6.5 – 9.4) 274,275,283,285,288,295,311, CCPA (7.7 – 8.1) 288,308	apadenoson (9.3) 310, CGS 21680 (6.7 – 8.1) 270,276,283,288,299,302,303,308	Bay60-6583 (8.0 – 8.52) 277	IB-MECA (8.7 – 9.2) 278,281,302,320, Cl-IB-MECA (8.0 – 8.9) 271,289,298
(Sub)family-selective antagonists (pKi)	XAC (pKd 7.5) 279, CGS 15943 (8.46) 309	XAC (8.4 – 9.0) 276,302, CGS 15943 (7.7 – 9.4) 276,299,302,309	XAC (pA2 7.9) 265, CGS 15943 (pA2 7.8) 265, XAC (6.9 – 8.8) 268,292,293,302,306,314, CGS 15943 (6.0 – 8.1) 267,292,293,302,309,314	CGS 15943 (7.0 – 7.9) 301,302,309,320, XAC (7.0 – 7.4) 302,312,320
Selective antagonists (pKi)	PSB36 (9.9 - Rat) 264, SLV320 (9.0) 297, DPCPX (7.4 – 9.2) 275,286,308,311,322	SCH442416 (8.4 – 10.3) 313,316, ZM-241385 (8.8 – 9.1) 309, SCH 58261 (8.3 – 9.2) 276,303,309	PSB-0788 (9.4) 269, PSB603 (9.26) 269, MRS1754 (8.8) 292,300, PSB1115 (7.27) 284	MRS1220 (8.2 – 9.2) 289,301,315,325, VUF5574 (8.39) 318, MRS1523 (7.7) 304, MRS1191 (7.5) 289,294,305
Radioligands (Kd)	[3H]CCPA (Agonist, Full agonist) (6.31x10-10 M) 302,311, [3H]DPCPX (Antagonist) (6x10-10 – 1.2x10-9 M) 274,278,302,309,311,317	[3H]ZM 241385 (Antagonist) (8x10-10 – 1.8x10-9 M) 266,282, [3H]CGS 21680 (Agonist, Full agonist) (1.6x10-8 – 2.2x10-8 M) 291,321	[3H]MRS1754 (Antagonist) (1.58x10-10 M) 292	[125I]AB-MECA (Agonist, Full agonist) (6x10-10 – 1x10-9 M) 309,320

Comments

Adenosine inhibits many intracellular ATP-utilising enzymes, including adenylyl cyclase (P-site). A pseudogene exists for the A_2B adenosine receptor (ADORA2BP1) with 79% identity to the A_2B adenosine receptor cDNA coding sequence, but which is unable to encode a functional receptor 290. DPCPX also exhibits antagonism at A_2B receptors (pK_i ca. 7,265,302). Antagonists at A₃ receptors exhibit marked species differences, such that only MRS1523 and MRS1191 are selective at the rat A₃ receptor. In the absence of other adenosine receptors, [3H]DPCPX and [3H]ZM 241385 can also be used to label A_2B receptors (K_D ca. 30 and 60 nM respectively). [125I]AB-MECA also binds to A₁ receptors 302. [3H]CGS 21680 is relatively selective for A_2A receptors, but may also bind to other sites in cerebral cortex 273,296. [3H]NECA binds to other non-receptor elements, which also recognise adenosine 307. XAC-BY630 has been described as a fluorescent antagonist for labelling A₁ adenosine receptors in living cells, although activity at other adenosine receptors was not examined 272.

Adhesion Class GPCRs

Overview

Adhesion GPCRs are structurally identified on the basis of a large extracellular region, similar to the Class B GPCR, but which is linked to the 7TM region by a "stalk" motif containing a GPCR proteolytic site. The N-terminus often shares structural homology with proteins such as lectins and immunoglobulins, leading to the term adhesion GPCR 326,331.

Nomenclature	HGNC, UniProt	Comment
BAI1	BAI1, O14514	BAI1 is reported to respond to phosphatidylserine 329.
BAI2	BAI2, O60241	–
BAI3	BAI3, O60242	–
CD97	CD97, P48960	–
CELSR1	CELSR1, Q9NYQ6	–
CELSR2	CELSR2, Q9HCU4	–
CELSR3	CELSR3, Q9NYQ7	–
ELTD1	ELTD1, Q9HBW9	–
EMR1	EMR1, Q14246	–
EMR2	EMR2, Q9UHX3	–
EMR3	EMR3, Q9BY15	–
EMR4P	EMR4P, Q86SQ3	–
GPR56	GPR56, Q9Y653	Reported to bind tissue transglutaminase 2 330 and collagen, which activates the G12/13 pathway 328.
GPR64	GPR64, Q8IZP9	–
GPR97	GPR64, Q8IZP9	–
VLGR1	GPR98, Q8WXG9	Loss-of-function mutations are associated with Usher syndrome, a sensory deficit disorder 327.
GPR110	GPR110, Q5T601	–
GPR111	GPR111, Q8IZF7	–
GPR112	GPR112, Q8IZF6	–
GPR113	GPR113, Q8IZF5	–
GPR114	GPR114, Q8IZF4	–
GPR115	GPR115, Q8IZF3	–
GPR116	GPR116, Q8IZF2	–
GPR123	GPR123, Q86SQ6	–
GPR124	GPR124, Q96PE1	–
GPR125	GPR125, Q8IWK6	–
GPR126	GPR126, Q86SQ4	–
GPR128	GPR128, Q96K78	–
GPR133	GPR133, Q6QNK2	–
GPR144	GPR144, Q7Z7M1	–
LPHN1	LPHN1, O94910	–
LPHN2	LPHN2, O95490	–
LPHN3	LPHN3, Q9HAR2	–

Adrenoceptors

Overview

α₁-Adrenoceptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Adrenoceptors; 340) are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline with equal potency. phenylephrine, methoxamine and cirazoline are agonists selective for α₁-adrenoceptors relative to α₂-adrenoceptors, while prazosin (8.5–10.5) and corynanthine (6.5–7.5) are antagonists considered selective for α₁-adrenoceptors relative to α₂-adrenoceptors. [3H]prazosin (0.25 nM) and [125I]HEAT (0.1 nM; also known as BE2254) are relatively selective radioligands. The α_1A-adrenoceptor antagonist (+)-niguldipine also has high affinity for L-type Ca²⁺ channels. The conotoxin ρ-TIA acts as a negative allosteric modulator at the α_1B-adrenoceptor 396, while the snake toxin ρ-Da1a acts as a selective competitive antagonist at the α_1A-adrenoceptor 386. Fluorescent derivatives of prazosin (Bodipy PL-prazosin – QAPB) are increasingly used to examine cellular localisation of α₁-adrenoceptors. The vasoconstrictor effects of selective α1-adrenoceptor agonists have led to their use as nasal decongestants; antagonists are used to treat hypertension (doxazosin, prazosin) and benign prostatic hyperplasia (alfuzosin, tamsulosin). The combined α₁- and β₂-adrenoceptor antagonist carvedilol is widely used to treat congestive heart failure, although the contribution of α₁-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs possess α₁-adrenoceptor blocking properties that are believed to contribute to side effects such as orthostatic hypotension and extrapyramidal effects.

Nomenclature	α1A-adrenoceptor	α1B-adrenoceptor	α1D-adrenoceptor
HGNC, UniProt	ADRA1A, P35348	ADRA1B, P35368	ADRA1D, P25100
Principal transduction	Gq/11	Gq/11	Gq/11
Selective agonists (pKi)	dabuzalgron (7.4) 339, A61603 (pIC50 7.8–8.4) 355,369	–	–
Selective antagonists (pKi)	silodosin (10.4) 397, tamsulosin (10.0–10.7) 343,346,355,397,410, (+)-niguldipine (9.1–10.0) 355,397, ρ-Da1a (9.22) 386, SNAP5089 (8.8–9.4) 360,371,409	–	BMY-7378 (8.7–9.1) 342,413

Comments

Adrenoceptors, α₁

The clone originally called the α_1C-adrenoceptor corresponds to the pharmacologically defined α_1A-adrenoceptor 361. Some tissues possess α_1A-adrenoceptors (termed αα1_L-adrenoceptors 355,381) that display relatively low affinity in functional and binding assays for prazosin (pK_i < 9) indicative of different receptor states or locations. α_1A-adrenoceptor C-terminal splice variants form homo- and heterodimers, but fail to generate a functional α_1L-adrenoceptor 387. A study suggests that the &alpha_1L-adenoceptor phenotype may result from the interaction of α_1A-adrenoceptors with cysteine-rich epidermal growth factor-like domain 1α (CRELD1α) 382,383,404. α_1D-Adrenoceptors form heterodimers with α_1B- or β₂-adrenoceptors that show increased cell-surface expression 402. Heterodimers formed between α_1D- and α_1B-adrenoceptors have distinct functional properties 359. Recombinant α_1D-adrenoceptors have been shown in some heterologous systems to be mainly located intracellularly but cell-surface localization is attained by truncation of the N-terminus, or by co-expression of α1B- or β2-adrenoceptors to form heterodimers 359,402. In smooth muscle of native blood vessels all three α₁-adrenoceptor subtypes are located on the surface and intracellularly 377,378.

Signalling is predominantly via G_q/11 but α₁-adrenoceptors also couple to G_i/o, G_s and G_12/13. Several ligands activating α_1A-adrenoceptors display ligand directed signalling bias. For example, oxymetazoline is a full agonist for extracellular acidification rate (ECAR) and a partial agonist for Ca2+ release but does not stimulate cAMP production. Phenylephrine is biased toward ECAR versus Ca2+ release or cAMP accumulation but not between Ca2+ release and cAMP accumulation 351. There are also differences between subtypes in coupling efficiency to different pathways – e.g. in some systems coupling efficiency to Ca²⁺ signalling is α_1A > α_1B > α_1D, but for MAP kinase signalling is α_1D > α_1A > α_1B. In vascular smooth muscle, potency of agonists is related to the predominant subtype, α_1D- conveying greater sensitivity than α1A-adrenoceptors 354.

Adrenoceptors, α₂

α₂-Adrenoceptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Adrenoceptors; 340) are activated by endogenous agonists with a relative potency of (-)-adrenaline > (-)-noradrenaline. UK14304 (brimonidine) and BHT920 are agonists selective for α₂-adrenoceptors relative to α₁-adrenoceptors, rauwolscine (9.0) and yohimbine (9.0) are antagonists selective for α₂-adrenoceptors relative to α₁-adrenoceptors. [3H]rauwolscine (1 nM), [3H]UK14304 (5 nM) and [3H]RX821002 (0.5 nM and 0.1 nM at α_2C) are relatively selective radioligands. There is species variation in the pharmacology of the α_2A-adrenoceptor; for example, yohimbine, rauwolscine and oxymetazoline have an ∼20-fold lower affinity for rat, mouse and bovine α_2A-adrenoceptors compared to the human receptor. These α_2A orthologues are sometimes referred to as α_2D-adrenoceptors. Multiple mutations of α₂-adrenoceptors have been described, some of which are associated with alterations in function. Presynaptic α₂-adrenoceptors are widespread in the nervous system and regulate many functions, hence the multiplicity of actions. The effects of classical (not subtype selective) α₂-adrenoceptor agonists such as clonidine, guanabenz and UK14304 (brimonidine) on central baroreflex control (hypotension and bradycardia), hypnotic, analgesic, seizure modulation and platelet aggregation are mediated by α_2A-adrenoceptors. clonidine has been used as an anti-hypertensive and also to counteract opioid withdrawal. Actions on imidazoline receptors may contribute to the pharmacological effects of clonidine. α₂-Adrenoceptor agonists such as dexmedetomidine have been widely used as sedatives and analgesics in veterinary medicine (also xylazine) and are now used frequently in humans. α₂-Adrenoceptor antagonists are relatively little used therapeutically although yohimbine has been used to treat erectile dysfunction and several anti-depressants (cyanopindolol, mirtazepine) that block α₂-adrenoceptors may work through this mechanism. The roles of α_2B and α_2C-adrenoceptors are less clear but the α_2B subtype appears to be involved in neurotransmission in the spinal cord and α_2C in regulating catecholamine release from adrenal chromaffin cells.

Nomenclature	α2A-adrenoceptor	α2B-adrenoceptor	α2C-adrenoceptor
HGNC, UniProt	ADRA2A, P08913	ADRA2B, P18089	ADRA2C, P18825
Principal transduction	Gi/o	Gi/o	Gi/o
Selective agonists (pKi)	oxymetazoline (Partial agonist) (8.0) 365,403, guanfacine (7.1) 374	–	–
Selective antagonists (pKi)	BRL 44408 (8.2–8.77) 403,414	imiloxan (7.3 - Rat) 379	JP1302 (pKB 7.8) 392

Comments

ARC-239 (pKi 8.0) and prazosin (pKi 7.5) show selectivity for α_2B- and α2_C-adrenoceptors over α_2A-adrenoceptors.oxymetazoline is a reduced efficacy agonist and is one of many α₂-adrenoceptor agonists that are imidazolines or closely related compounds. Other binding sites for imidazolines, distinct from α₂-adrenoceptors, and structurally distinct from the 7TM adrenoceptors, have been identified and classified as I₁, I₂ and I₃ sites; catecholamines have a low affinity, while rilmenidine and moxonidine are selective ligands for these sites, evoking hypotensive effects in vivo. I₁-imidazoline receptors are involved in central inhibition of sympathetic tone, I₂-imidazoline receptors are an allosteric binding site on monoamine oxidase B, and I₃-imidazoline receptors regulate insulin secretion from pancreatic β-cells. α_2A-adrenoceptor stimulation reduces insulin secretion from β-islets 412, with a polymorphism in the 5′-UTR of the ADRA2A gene being associated with increased receptor expression in β-islets and heightened susceptibility to diabetes 391.

α_2A- and α_2c-adrenoceptors form homodimers 398. Heterodimers between α_2A- and either the α_2c-adrenoceptor or μ opioid peptide receptor exhibit altered signalling and trafficking properties compared to the individual receptors 398,401,405. Signalling by α₂-adrenoceptors is primarily via G_i/o, however the α_2A-adrenoceptor also couples to G_s 350. Imidazoline compounds display bias at the α_2A-adrenoceptor when assayed by [³⁵S] GTPγS binding compared to inhibition of cAMP accumulation 384. The noradrenaline reuptake inhibitor desipramine acts directly on the α_2A-adrenoceptor, promoting internalisation via recruitment of β-arrestin without activating G proteins 345.

Adrenoceptors, β

β-Adrenoceptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Adrenoceptors, 340) are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. isoprenaline is a synthetic agonist selective for β-adrenoceptors relative to α₁- and α₂-adrenoceptors, while propranolol (pK_i 8.2–9.2) and cyanopindolol (pK_i 10.0–11.0) are relatively selective antagonists. (-)-noradrenaline, xamoterol and (-)-Ro 363 are agonists that show selectivity for β₁- relative to β₂-adrenoceptors. Pharmacological differences exist between human and mouse β₃-adrenoceptors, and the ‘rodent selective’ agonists BRL 37344 and CL316243 have low efficacy at the human β₃-adrenoceptor whereas CGP 12177 and L 755507 activate human β₃-adrenoceptors 393. β₃-Adrenoceptors are relatively resistant to blockade by propranolol (pK_i 5.8–7.0), but can be blocked by high concentrations of bupranolol (pK_i 8.65,394). SR59230A has reasonably high affinity at β₃-adrenoceptors 375, but does not discriminate well between the three β-adrenoceptor subtypes 341 and has been reported to have lower affinity for the β₃-adrenoceptor in some circumstances 368. [¹²⁵I]-cyanopindolol, [¹²⁵I]-hydroxybenzylpindolol and [³H]-alprenolol are high affinity radioligands widely used to label β₁- and β₂-adrenoceptors and β₃-adrenoceptors can be labelled with higher concentrations (nM) of [¹²⁵I]-cyanopindolol in the presence of appropriate concentrations of β₁- and β₂-adrenoceptor antagonists. Fluorescent ligands such as BODIPY-TMR-CGP12177 are also increasingly being used to track β-adrenoceptors at the cellular level 335. Somewhat selective β₁-adrenoceptor selective agonists (denopamine, dobutamine) are used short-term to treat cardiogenic shock but, in the longer term, reduce survival. β₁-Adrenoceptor-preferring antagonists are used to treat hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol), cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol). Cardiac failure is also succesfully treated with carvedilol which blocks both β₁- and β₂-adrenoceptors, as well as α₁-adrenoceptors. β₂-Adrenoceptor-selective agonists are powerful bronchodilators widely used to treat respiratory disorders. There are both short (salbutamol, terbutaline) and long acting drugs (formoterol, salmeterol). Although many first generation β-adrenoceptor antagonists (propranolol) block both β₁- and β₂-adrenoceptors there are no β₂-adrenoceptor-selective antagonists used therapeutically. Although potentially useful for the treatment of obesity, there are no β₃-adrenoceptor-selective agonists used for this purpose currently. Several β₃-adrenoceptor agonists (mirabegron, amibegron and solabegron) are used to control overactive bladder syndrome.

Nomenclature	β1-adrenoceptor	β2-adrenoceptor	β3-adrenoceptor
HGNC, UniProt	ADRB1, P08588	ADRB2, P07550	ADRB3, P13945
Principal transduction	Gs	Gs	Gs
Rank order of potency	(-)-noradrenaline > (-)-adrenaline	(-)-adrenaline > (-)-noradrenaline	(-)-noradrenaline = (-)-adrenaline
Endogenous agonists (pKi)	noradrenaline (6.0) 356	–	–
Selective agonists (pKi)	(-)-Ro 363 (8.0) 380, xamoterol (Partial agonist) (7.0) 364, denopamine (Partial agonist) (5.8) 364,400	formoterol (pEC50 10.08) 334, salmeterol (pEC50 9.9) 334, zinterol (pEC50 9.48) 334, procaterol (pEC50 8.43) 334	carazolol (8.7) 376, BRL 37344 (6.4–7.0) 338,348,362,376, CGP 12177 (Partial agonist) (6.1–7.3) 338,373,376,380, CL316243 (5.2) 411, L 755507 (pEC50 10.1) 334, L742791 (pEC50 8.8) 408, SB251023 (pEC50 7.14 - Mouse) 363
Selective antagonists (pKi)	CGP 20712A (8.5–9.2) 332,341,373, betaxolol (8.8) 373, atenolol (6.7–7.6) 332,366,373	ICI 118551 (Inverse agonist) (9.2–9.5) 332,335,373	L-748337 (8.4) 341, SR59230A (6.9–8.4) 341,347,362
Radioligands (Kd)	[125I]ICYP (Antagonist, it is necessary to use an excess of a β2-AR-selective ligand such as ICI 118551 to allow visualisation of β1-AR binding in native tissue) (4.99x10-12–3.28x10-11 M) 373,395	[125I]ICYP (Antagonist, it is necessary to use an excess of a β1-AR-selective ligand such as CGP20712A to allow visualisation of β2-AR binding in native tissues) (7.9x10-12 M) 373,395	[125I]ICYP (Agonist, Partial agonist) (1.58x10-10–6.31x10-10 M) 373,380,385,395,399
Comment	The agonists indicated have less than two orders of magnitude selectivity 334.	–	Agonist SB251023 has a pEC50 of 6.9 for the splice variant of the mouse β3 receptor, β3b 363.

Comments

Radioligand binding with [125I]ICYP can be used to define β₁- or β₂-adrenoceptors when conducted in the presence of a ‘saturating’ concentration of either a β₁- or β₂-adrenoceptor-selective antagonist. [3H]CGP12177 or [3H]dihydroalprenolol can be used in place of [125I]ICYP. Binding of a fluorescent analogue of CGP 12177 to β₂-adrenoceptors in living cells has been described 336. [125I]ICYP at higher (nM) concentrations can be used to label β₃-adrenoceptors in systems where there are few if any other β-adrenoceptor subtypes.Pharmacological differences exist between human and mouse β₃-adrenoceptors, and the ‘rodent selective’ agonists BRL 37344 and CL316243 have low efficacy at the human β₃-adrenoceptor whereas CGP 12177 and L 755507 activate human β3-adrenoceptors 394. The β₃-adrenoceptor has an intron in the coding region, but splice variants have only been described for the mouse 352, where the isoforms display different signalling characteristics 363. There are 3 β-adrenoceptors in turkey (termed the tβ, tβ3c and tβ4c) that have a pharmacology that differs from the human β-adrenoceptors 333. The ‘putative β₄-adrenoceptor’ is not a novel receptor but is likely to represent an alternative site of interaction of CGP 12177 and other nonconventional partial agonists at β₁-adrenoceptors, since ‘putative β₄-adrenoceptor'-mediated agonist effects of CGP 12177 are absent in mice lacking β₁-adrenoceptors 367,370. Numerous polymorphisms have been described for the three β-adrenoceptors; some are associated with alterations in agonist-evoked signalling, trafficking, altered diseases susceptibility and/or altered responses to pharmacotherapy.

All β-adrenoceptors couple to G_s (activating adenylyl cyclase and elevating cAMP levels), but it is also clear that they activate other G proteins such as G_i and many other G protein-independent signalling pathways, including β-arrestins, which may in turn lead to activation of mitogen-activated protein kinases. Many antagonists at β₁- and β₂-adrenoceptors are agonists at β₃-adrenoceptors (CL316243, CGP 12177 and carazolol). Many ‘antagonists’ that block agonist-stimulated cAMP accumulation, for example carvedilol and bucindolol, are able to activate mitogen-activated protein kinase pathways 337,353,357,358,393,394 and thus display ‘protean agonism’. bupranolol appears to act as a neutral antagonist in most systems so far examined. Agonists also display biased signalling at the β₂-adrenoceptor via G_s or β-arrestins 349.

The X-ray crystal structures have been described of the agonist bound 406 and antagonist bound forms of the β₁- 407, agonist-bound 344 and antagonist-bound forms of the β₂-adrenoceptor 388,390, as well as a fully active agonist-bound, G_s protein-coupled β₂-adrenoceptor 389. carvedilol and bucindolol bind to an extended site of the β₁-adrenoceptor involving contacts in TM2, 3, and 7 and extracellular loop 2 that may facilitate coupling to β-arrestins 407. Compounds displaying β-arrestin-biased signalling at the β₂-adrenoceptor also have a greater effect on the conformation of TM7, whereas full agonists for G_s coupling promote movement of TM5 and TM6 372.

Angiotensin receptors

Overview

The actions of angiotensin II (AGT, P01019) (Ang II) are mediated by AT₁ and AT₂ receptors (nomenclature agreed by the NC-IUPHAR Subcommittee on Angiotensin Receptors; 424), which have around 30% sequence similarity. Endogenous ligands are angiotensin II (AGT, P01019) and angiotensin III (AGT, P01019) (Ang III), while angiotensin I (AGT, P01019) is weakly active in some systems.

Nomenclature	AT1 receptor	AT2 receptor
HGNC, UniProt	AGTR1, P30556	AGTR2, P50052
Principal transduction	Gq/11	Gi/Go, Tyr & Ser/Thr phosphatases
Selective agonists (pKi)	L-162313 (pIC50 7.85–7.92) 433	[p-aminoPhe6]ang II (pKd 9.1–9.4 - Rat) 426,434, CGP42112 (pIC50 9.63) 417
Selective antagonists (pKi)	candesartan (pIC50 9.5–9.7) 436, irbesartan (pIC50 8.7–8.8) 436, valsartan (pIC50 8.61) 425, eprosartan (pIC50 8.4–8.8) 429, EXP3174 (pIC50 7.4–9.5) 435,436, losartan (pIC50 7.4–8.7) 426,435	PD123319 (pKd 8.7–9.2) 426,427,440, PD123177 (pIC50 8.5–9.5 - Rat) 419,422,428
Radioligands (Kd)	[3H]eprosartan (Antagonist), [3H]A81988 (Antagonist) (5.7x10−10 M - Rat) 430, [3H]L158809 (Antagonist) (6.6x10−10 M - Rat) 421, [125I]EXP985 (Antagonist) (1.49x10−9 M - Rat) 423, [3H]losartan (Antagonist) (6.2x10−9 M - Rat) 420, [3H]valsartan (Antagonist) (IC50 1x10−9 – 1.58x10−9 M) 437	[125I]CGP42112 (Agonist, Full agonist) (2.51x10−11 M) 426,438,439

Comments

AT₁ receptors are predominantly coupled to Gq_/11, however they are also linked to arrestin recruitment and stimulate G protein-independent arrestin signalling 431. Most species express a single AGTR1 gene, but two related agtr1a and agtr1b receptor genes are expressed in rodents. The AT₂ receptor counteracts several of the growth responses initiated by the AT₁ receptors. The AT₂ receptor is much less abundant than the AT₁ receptor in adult tissues and is upregulated in pathological conditions.

There is also evidence for an AT₄ receptor that specifically binds angiotensin IV (AGT) and is located in the brain and kidney. An additional putative endogenous ligand for the AT₄ receptor has been described (LVV-hemorphin (HBB, P68871), a globin decapeptide) 432. The AT₁ and bradykinin B2 receptors have been proposed to form a heterodimeric complex 416. The antagonist activity of CGP42112 has also been reported 415. AT₁ receptor antagonists bearing substituted 4-phenylquinoline moieties have been synthesized, which bind to AT₁ receptors with nanomolar affinity and are slightly more potent than losartan in functional studies 418.

Apelin receptor

Overview

The apelin receptor (APJ, nomenclature as agreed by NC-IUPHAR on apelin receptors, 449) responds to apelin, a 36 amino-acid peptide derived initially from bovine stomach. apelin-36 (APLN, Q9ULZ1), apelin-13 (APLN, Q9ULZ1) and [Pyr1]apelin-13 (APLN, Q9ULZ1) are the predominant endogenous ligands which are cleaved from a 77 amino-acid precursor peptide (APLN, Q9ULZ1) by a so far unidentified enzymatic pathway 450.

Nomenclature	HGNC, UniProt	Principal transduction	Rank order of potency	Endogenous agonists (pKi)	Radioligands (Kd)
apelin receptor	APLNR, P35414	Gi/o	[Pyr1]apelin-13 ≥ apelin-13 > apelin-36 443,450	apelin-13 (Selective) (pIC50 8.8 – 9.5) 443,444,448, apelin-17 (Selective) (pIC50 7.9 – 9.02) 442,448, apelin-36 (Selective) (pIC50 8.2 – 8.6) 443,444,446,448, [Pyr1]apelin-13 (Selective) (pIC50 7.0 – 8.8) 446,448	[125I][Nle75,Tyr77]apelin-36 (human) (Agonist, Full agonist) (6.3x10-12 M) 446, [125I][Glp65Nle75,Tyr77]apelin-13 (Agonist, Full agonist) (2.23x10-11 M) 444, [125I](Pyr1)apelin-13 (Agonist, Full agonist) (3x10-10 M) 445, [125I]apelin-13 (Agonist, Full agonist) (7x10-10 M) 443, [3H](Pyr1)[Met(0)11]-apelin-13 (Agonist, Full agonist) (2.7x10-9 M) 448

Comments

Potency order determined for heterologously expressed human APJ receptor (pD₂ values range from 9.5 to 8.6). APJ may also act as a co-receptor with CD4 for isolates of human immunodeficiency virus, with apelin blocking this function 441. A modified apelin-13 peptide, apelin-13(F13A) was reported to block the hypotensive response to apelin in rat in vivo 447, however, this peptide exhibits agonist activity in HEK293 cells stably expressing the recombinant APJ receptor 443.

Bile acid receptor

Overview

The bile acid receptor (GPBA) responds to bile acids produced during the liver metabolism of cholesterol. Selective agonists are promising drugs for the treatment of metabolic disorders, such as type II diabetes, obesity and atherosclerosis.

Nomenclature	HGNC, UniProt	Principal transduction	Rank order of potency	Selective agonists (pKi)
GPBA receptor	GPBAR1, Q8TDU6	Gs 454	lithocholic acid > deoxycholic acid > chenodeoxycholic acid, cholic acid 452,454	betulinic acid (pEC50 5.98) 451, oleanolic acid (pEC50 5.65) 455

Comments

The triterpenoid natural product betulinic acid has also been reported to inhibit inflammatory signalling through the NFκB pathway 456. Disruption of GPBA expression is reported to protect from cholesterol gallstone formation 457. A new series of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides have been reported as highly potent agonists 453.

Bombesin receptors

Overview

Bombesin receptors (nomenclature recommended by the NC-IUPHAR Subcommittee on bombesin receptors, 462) are activated by the endogenous ligands gastrin-releasing peptide (GRP, P07492) (GRP), NMB (NMB, P08949) (NMB) and GRP-(18–27) (GRP, P07492) (previously named neuromedin C). bombesin is a tetradecapeptide, originally derived from amphibians. These receptors couple primarily to the G_q/11 family of G proteins (but see also 463). Activation of BB₁ and BB₂ receptors causes a wide range of physiological actions, including the stimulation of tissue growth, smooth–muscle contraction, secretion and many central nervous system effects 469. A physiological role for the BB₃ receptor has yet to be fully defined although receptor knockout experiments suggest a role in energy balance and the control of body weight 462.

Nomenclature	BB1 receptor	BB2 receptor	BB3 receptor
HGNC, UniProt	NMBR, P28336	GRPR, P30550	BRS3, P32247
Principal transduction	Gq/11	Gq/11	Gq/11
Endogenous agonists (pKi)	NMB (Selective) (8.1 – 10.3) 458,468	gastrin-releasing peptide (Selective) (6.34 – 8.21) 458,468	–
Selective antagonists (pKi)	dNal-cyc(Cys-Tyr-dTrp-Orn-Val)-Nal-NH2, PD 165929 (pKd 8.2) 460, PD 168368 (pIC50 9.24 – 9.6) 459, D-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Nal-NH2 (pIC50 6.22 – 6.56) 459,468	[D-Phe6,Cpa14,ψ13–14]bombesin-(6–14), JMV594 (pIC50 8.7 - Mouse) 464,470, Ac-GRP-(20–26)-methylester (pIC50 8.4 - Mouse) 461	–
Selective agonists (pKi)	–	–	[D-Tyr6,Apa-4Cl11,Phe13,Nle14]bombesin-(6–14) (8.1) 466
Radioligands (Kd)	[125I]BH-NMB, [125I][Tyr4]bombesin	[125I]GRP (human), [125I][D-Tyr6]bombesin-(6–13)-methyl ester (Antagonist) (5.3x10-10 M - Mouse) 465, [125I][Tyr4]bombesin (Agonist, Full agonist) (6.31x10-9 M) 458	[125I][D-Tyr6,β-Ala11,Phe13,Nle14]bombesin-(6–14) (Agonist, Full agonist) (1x10-8 – 3.98x10-9 M) 467

Comments

All three subtypes may be activated by [D-Phe6,β-Ala11,Phe13,Nle14]bombesin-(6–14) 467. [D-Tyr6,Apa-4Cl11,Phe13,Nle14]bombesin-(6–14) has more than 200-fold selectivity for BB₃ receptors over BB₁ and BB₂ 466.

Bradykinin receptors

Overview

Bradykinin (or kinin) receptors (nomenclature recommended by the NC-IUPHAR subcommittee on bradykinin (kinin) receptors, 478) are activated by the endogenous peptides bradykinin (KNG1, P01042) (BK), [des-Arg9]bradykinin (KNG1, P01042), Lys-BK (kallidin (KNG1, P01042)), [des-Arg10]kallidin (KNG1, P01042), T-kinin (KNG1, P01042) (Ile-Ser-BK), [Hyp3]-BK (KNG1, P01042) and Lys-[Hyp3]-bradykinin (KNG1, P01042). The variation in affinity or inactivity of B₂ receptor antagonists could reflect the existence of species homologues of B₂ receptors.

Nomenclature	B1 receptor	B2 receptor
HGNC, UniProt	BDKRB1, P46663	BDKRB2, P30411
Principal transduction	Gq/11	Gq/11
Rank order of potency	[des-Arg10]kallidin > [des-Arg9]bradykinin = kallidin > bradykinin	kallidin > bradykinin >> [des-Arg9]bradykinin, [des-Arg10]kallidin
Endogenous agonists (pKi)	[des-Arg10]kallidin (KNG1, P01042) (Selective) (9.6 – 10.0) 471,472,477	–
Selective agonists (pKi)	[Sar,D-Phe8,des-Arg9]bradykinin (5.7) 477	[Hyp3,Tyr(Me)8]BK, [Phe8,ψ(CH2-NH)Arg9]BK
Selective antagonists (pKi)	R 914 (pA2 8.6) 474, R-715 (pA2 8.5) 475, B-9958 (9.2 – 10.3) 473,480, [Leu9,des-Arg10]kallidin (9.1 – 9.3) 471,472	icatibant (pA2 8.4) 476, FR173657 (pA2 8.2) 481, anatibant (8.2) 479
Radioligands (Kd)	[3H]Lys-[Leu8][des-Arg9]BK (Antagonist), [125I]Hpp-desArg10HOE140 (1x10-10 M), [3H]Lys-[des-Arg9]BK (Agonist, Full agonist) (4x10-10 M)	[125I][Tyr8]bradykinin, [3H]BK (human, mouse, rat) (Agonist, Full agonist) (3.99x10-10 M - Mouse) 482, [3H]NPC17731 (Antagonist) (3.9x10-10 – 7.7x10-10 M) 483,484

Calcitonin receptors

Overview

Calcitonin (CT), amylin (AMY), calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on CGRP, AM, AMY, and CT receptors, 495,504) are generated by the genes CALCR (which codes for the CT receptor (CTR),) and CALCRL (which codes for the calcitonin receptor-like receptor, CLR, previously known as CRLR,). Their function and pharmacology are altered in the presence of RAMPs (receptor activity-modifying protein), which are single TM domain proteins of ca. 130 amino acids, identified as a family of three members; RAMP1, RAMP2 and RAMP3. There are splice variants of CTR; these in turn produce variants of the AMY receptor 504. The endogenous agonists are the peptides CT (CALCA, P01258), α-CGRP (CALCA, P06881) (formerly known as CGRP-I), β-CGRP (CALCB, P10092) (formerly known as CGRP-II), AMY (IAPP, P10997) (occasionally called islet-amyloid polypeptide, diabetes-associated polypeptide), AM (ADM, P35318) and AM2/IMD (ADM2, Q7Z4H4) (AM2/IMD). There are species differences in peptide sequences, particularly for the CTs. CTR-stimulating peptide (CRSP) is another member of the family with selectivity for the CTR but it is not expressed in humans 497. BIBN4096BS (also known as olcegepant, pKi∼10.5) and MK-0974 (also known as telcagepant, pKi∼9) are the most selective antagonists available, having a high selectivity for CGRP receptors, with a particular preference for those of primate origin.

CLR by itself binds no known endogenous ligand, but in the presence of RAMPs it gives receptors for CGRP, AM and AM2/IMD.

Nomenclature	CGRP receptor	AM1 receptor	AM2 receptor
Subunits	RAMP1 (Accessory protein), calcitonin receptor-like receptor	RAMP2 (Accessory protein), calcitonin receptor-like receptor	RAMP3 (Accessory protein), calcitonin receptor-like receptor
Principal transduction	Gs	Gs	Gs
Rank order of potency	α-CGRP > AM ≥ AM2/IMD > AMY ≥ CT (salmon)	AM > AMY > α-CGRP, AM2/IMD > CT (salmon)	AM ≥ AM2/IMD ≥ α-CGRP > AMY > CT (salmon)
Endogenous agonists (pKi)	β-CGRP (9.9 – 11.0) 485,501, α-CGRP (9.7 – 10.0) 485,501	AM (8.3 – 9.2) 485,501	AM (8.3 – 9.0) 485,491
Selective antagonists (pKi)	BIBN4096BS (10.2 – 10.7) 489,493,494,500, MK-0974 (9.1) 506	AM-(22-52) (human) (7.0 – 7.8) 485,494,501	–
Radioligands (Kd)	[125I]αCGRP (mouse, rat) (Agonist, Full agonist), [125I]αCGRP (human) (Agonist, Full agonist) (1x10−10 M)	[125I]AM (rat) (Agonist, Full agonist) (1x10−10 – 1x10−9 M)	[125I]AM (rat) (Agonist, Full agonist) (1x10−10 – 1x10−9 M)

Nomenclature	CT receptor	AMY1 receptor	AMY2 receptor	AMY3 receptor
HGNC, UniProt	CALCR, P30988	–	–	–
Subunits	–	RAMP1 (Accessory protein), CT receptor	RAMP2 (Accessory protein), CT receptor	RAMP3 (Accessory protein), CT receptor
Principal transduction	Gs	Gs	Gs	Gs
Rank order of potency	CT (salmon) ≥ CT ≥ AMY, α-CGRP > AM, AM2/IMD	CT (salmon) ≥ AMY ≥ α-CGRP > AM2/IMD ≥ CT > AM	Poorly defined	CT (salmon) ≥ AMY > α-CGRP ≥ AM2/IMD ≥ CT > AM
Endogenous agonists (pKi)	CT (Selective) (pEC50 9.0 – 11.2) 486,487,492,498,499,503	AMY	AMY	AMY
Radioligands (Kd)	[125I]CT (salmon) (Agonist, Full agonist) (1x10−10 M), [125I]CT (human) (Agonist, Full agonist) (1x10−10 – 1x10−9 M)	[125I]BH-AMY (rat, mouse) (Agonist, Full agonist) (1x10−10 – 1x10−9 M)	[125I]BH-AMY (rat, mouse) (Agonist, Full agonist) (1x10−10 – 1x10−9 M)	[125I]BH-AMY (rat, mouse) (Agonist, Full agonist) (1x10−10 – 1x10−9 M)

Comments

It is important to note that a complication with the interpretation of pharmacological studies with AMY receptors in transfected cells is that most of this work has likely used a mixed population of receptors, encompassing RAMP-coupled CTR as well as CTR alone. This means that although in binding assays human CT (CALCA, P01258) has low affinity for ¹²⁵I-AMY binding sites, cells transfected with CTR and RAMPs can display potent CT functional responses. Transfection of human CTR with any RAMP can generate receptors with a high affinity for both salmon CT and AMY and varying affinity for different antagonists 488,492,493. The insert negative (and major) human CTR splice variant (hCT_(a)) with RAMP1 (i.e. the AMY_1(a) receptor) has a high affinity for CGRP, unlike hCT_(a)–RAMP3 (i.e. AMY_3(a) receptor) 488,492. However, the AMY receptor phenotype is RAMP-type, splice variant and cell-line-dependent 507. In particular, CGRP is a more potent agonist than AMY (IAPP, P10997) at increasing cAMP at the delta 47 hCT(a) receptor, when transfected with RAMP1 (to give the corresponding AMY1(a) receptor) in Cos 7 cells 505.

The ligands described represent the best available but their selectivity is limited, apart from BIBN4096BS and MK-0974. For example, AM has appreciable affinity for CGRP receptors. CGRP can show significant cross-reactivity at AMY receptors and AM₂ receptors. AM2/IMD also has high affinity for the AM₂ receptor 496. CGRP-(8-37) acts as an antagonist of CGRP (pK_i ∼8) and inhibits some AM and AMY responses (pK_i ∼6–7). It is weak at CT receptors. Salmon CT-(8-32) is an antagonist at both AMY and CT receptors. AC187, a salmon CT analogue, is also an antagonist at AMY and CT receptors. Human AM-(22-52) has some selectivity towards AM receptors, but with modest potency (pK_i ∼7), limiting its use 494. AM-(22-52) is slightly more effective at AM₁ than AM₂ receptors but this difference is not sufficient for this peptide to be a useful discriminator of the AM receptor subtypes.

Ligand responsiveness at CT and AMY receptors can be affected by receptor splice variation and can depend on the pathway being measured. Particularly for AMY receptors, relative potency can vary with the type and level of RAMP present and can be influenced by other factors such as G proteins 502,507.

G_s is a prominent route for effector coupling for CLR and CTR but other pathways (e.g. Ca²⁺, ERK, Akt), and G proteins can be activated 508. There is evidence that CGRP-RCP (a 148 amino-acid hydrophilic protein, ASL (P04424) is important for the coupling of CLR to adenylyl cyclase 490.

[¹²⁵I]-Salmon CT is the most common radioligand for CT receptors but it has high affinity for AMY receptors and is also poorly reversible. [¹²⁵I]-Tyr⁰-CGRP is widely used as a radioligand for CGRP receptors.

Some early literature distinguished between CGRP₁ and CGRP₂ receptors. It is now clear that CLCRL/RAMP1 represents the CGRP₁ subtype and is now known simply as the CGRP receptor 495. The CGRP₂ receptor is now considered to have arisen from the actions of CGRP at AM₂ and AMY receptors. This term should not be used 495.

Calcium-sensing receptors

Overview

The calcium-sensing receptor (CaS, provisional nomenclature) responds to extracellular calcium and magnesium in the millimolar range and to gadolinium and some polycations in the micromolar range 509. The sensitivity of CaS to primary agonists can be increased by aromatic L-amino acids 511 and also by elevated extracellular pH 520 or decreased extracellular ionic strength 521.

This receptor bears no sequence or structural relation to the plant calcium receptor, also called CaS.

Nomenclature	CaS receptor	GPRC6 receptor
HGNC, UniProt	CASR, P41180	GPRC6A, Q5T6X5
Principal transduction	Gq/11, Gi/o, G12/13 523	–
Amino-acid rank order of potency	L-phenylalanine, L-tryptophan, L-histidine > L-alanine > L-serine, L-proline, L-glutamic acid > L-aspartic acid (not L-lysine, L-arginine, L-leucine and L-isoleucine) 511	–
Cation rank order of potency	Gd3+ > Ca2+ > Mg2+ 509	–
Polyamine rank order of potency	spermine > spermidine > putrescine 522	–
Selective allosteric regulators	NPS 89636 (Negative) 515, NPS R-568 (Positive) (pKd 6.5) 517, calindol (Positive) (pKd 6.0 – 6.5) 513, AC265347 (Positive) (pEC50 7.6 – 8.1) 514, cinacalcet (Positive) (pEC50 7.3) 516, calindol (Positive) (pEC50 6.5) 518, NPS 2143 (Negative) (pIC50 7.1 – 7.4) 515,525, calhex 231 (Negative) (pIC50 6.4) 519	–
Comment	2-benzylpyrrolidine derivatives of NPS 2143 are also negative allosteric modulators of the calcium sensing receptor 525.	GPRC6 is a related Gq-coupled receptor which responds to basic amino acids 524,525.

Comments

Positive allosteric modulators of CaS are termed Type II calcimimetics and can suppress parathyroid hormone (PTH (PTH, P01270)) secretion 517. Negative allosteric modulators are called calcilytics and can act to increase PTH (PTH, P01270) secretion 515.

The central role of CaS in the maintenance of extracellular calcium homeostasis is seen most clearly in patients with loss-of-function CaS mutations who develop familial hypocalciuric hypercalcaemia (heterozygous mutation) or neonatal severe hyperparathyroidism (homozygous mutation) and in CaS null mice 510,512, which exhibit similar increases in PTH secretion and blood Ca2+ levels. A gain-of-function mutation in the CaS gene is associated with autosomal dominant hypocalcaemia.

Cannabinoid receptors

Overview

Cannabinoid receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Cannabinoid Receptors; 542) are activated by endogenous ligands that include N-arachidonoylethanolamine (anandamide), N-homo-γ-linolenoylethanolamine, N-docosatetra-7,10,13,16-enoylethanolamine and 2-arachidonoylglycerol. Potency determinations of endogenous agonists at these receptors are complicated by the possibility of differential susceptibility of endogenous ligands to enzymatic conversion 526.

Nomenclature	CB1 receptor	CB2 receptor
HGNC, UniProt	CNR1, P21554	CNR2, P34972
Principal transduction	Gi/o	Gi/o
(Sub)family-selective agonists (pKi)	CP55940 550, Δ9-tetrahydrocannabinol 550, HU-210 530, WIN55212-2 550	CP55940 550, Δ9-tetrahydrocannabinol 550, HU-210 530, WIN55212-2 550
Selective agonists (pKi)	arachidonyl-2-chloroethylamide (8.9 - Rat) 533, arachidonylcyclopropylamide (8.7 - Rat) 533, O-1812 (8.5 - Rat) 528, R-(+)-methanandamide (7.7 - Rat) 537	JWH-133 (8.5) 535,541, AM1241 (8.1) 555, L-759,633 (7.7 – 8.2) 531,548, L-759,656 (7.7 – 7.9) 531,548, HU-308 (7.6) 532
Selective antagonists (pKi)	rimonabant (7.9 – 8.7) 529,530,545,549,550, AM251 (8.1 - Rat) 539, AM281 (7.9 - Rat) 538, LY320135 (6.9) 529	SR144528 (8.3 – 9.2) 546,548, AM630 (7.5) 548
Radioligands (Kd)	[3H]rimonabant (Antagonist) (1x10−10 – 1.2x10−9 M - Rat) 527,534,536,543,547,551,554	–

Comments

Both CB₁ and CB₂ receptors may be labelled with [3H]CP55940 (0.5 nM; 550) and [3H]WIN55212-2 (2–2.4 nM; 552,553). anandamide is also an agonist at vanilloid receptors (TRPV1) and PPARs 540,556. There is evidence for an allosteric site on the CB₁ receptor 544. All of the compounds listed as antagonists behave as inverse agonists in some bioassay systems 542. For some cannabinoid receptor ligands, additional pharmacological targets that include GPR55 and GPR119 have been identified 542. Moreover, GPR18, GPR55 and GPR119, although showing little structural similarity to CB₁ and CB₂ receptors, respond to endogenous agents that are structurally similar to the endogenous cannabinoid ligands 542.

Chemerin receptor

Overview

The chemerin receptor is activated by the lipid-derived, anti-inflammatory ligand resolvin E1 (RvE1), which is the result of sequential metabolism of EPA by aspirin-modified cyclooxygenase and lipoxygenase 557,558. In addition, 2 GPCRs for resolvin D1 (RvD1) have been identified, FPR2/ALX, the lipoxin A₄ receptor, and GPR32, an orphan receptor 559.

Nomenclature	HGNC, UniProt	Principal transduction	Rank order of potency	Selective agonists (pKi)	Radioligands (Kd)	Comment
chemerin receptor	CMKLR1, Q99788	Not yet established	resolvin E1 > chemerin C-terminal peptide > 18R-HEPE > EPA 557	resolvin E1	[3H]resolvin E1 (Agonist) (1.1x10−8 M) 557,558	NC-IUPHAR has issued a recommendation for a formal nomenclature change for this receptor from CMKLR1 to ‘chemerin receptor’ based on new pairings with chemerin 560–562.

Chemokine receptors

Overview

Chemokine receptors (nomenclature agreed by NC-IUPHAR Subcommittee on Chemokine Receptors, 600,601) comprise a large subfamily of 7TM proteins that bind one or more chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes. Chemokine receptors can be divided by function into two main groups: G protein-coupled chemokine receptors, which mediate leukocyte trafficking, and “Atypical chemokine receptors”, which may signal through non-G protein-coupled mechanisms and act as chemokine scavengers to downregulate inflammation or shape chemokine gradients.

Chemokines in turn can be divided by structure into four subclasses by the number and arrangement of conserved cysteines. CC (also known as β-chemokines; n = 28), CXC (also known as α-chemokines; n = 17) and CX3C (n = 1) chemokines all have four conserved cysteines, with zero, one and three amino acids separating the first two cysteines respectively. C chemokines (n = 2) have only the second and fourth cysteines found in other chemokines. Chemokines can also be classified by function into homeostatic and inflammatory subgroups. Most chemokine receptors are able to bind multiple high-affinity chemokine ligands, but the ligands for a given receptor are almost always restricted to the same structural subclass. Most chemokines bind to more than one receptor subtype. Receptors for inflammatory chemokines are typically highly promiscuous with regard to ligand specificity, and may lack a selective endogenous ligand. G protein-coupled chemokine receptors are named acccording to the class of chemokines bound, whereas ACKR is the root acronym for atypical chemokine receptors. Listed are those human agonists with EC₅₀ values <50 nM in either Ca²⁺ flux or chemotaxis assays at human recombinant G protein-coupled chemokine receptors expressed in mammalian cell lines. There can be substantial cross-species differences in the sequences of both chemokines and chemokine receptors, and in the pharmacology and biology of chemokine receptors. Endogenous and microbial non-chemokine ligands have also been identified for chemokine receptors. Many chemokine receptors function as HIV co-receptors, but CCR5 is the only one demonstrated to play an essential role in HIV/AIDS pathogenesis. The tables include both standard chemokine receptor names 628 and the most commonly used aliases. Numerical data quoted are typically pK_i or pIC₅₀ values from radioligand binding to heterologously expressed receptors.

Nomenclature	CCR1	CCR2	CCR3	CCR4	CCR5
HGNC, UniProt	CCR1, P32246	CCR2, P41597	CCR3, P51677	CCR4, P51679	CCR5, P51681
Principal transduction	Gi/o	Gi/o	Gi/o	Gi/o	Gi/o
Endogenous agonists (pKi)	CCL13, CCL8, CCL3 (7.8 – 10.2) 571,572,588,630, CCL23 (Selective) (8.9) 571, CCL7 (8.1) 571,583, CCL5 (6.8 – 8.2) 572,588, CCL14 (7.4) 571, CCL15 (Selective) (pIC50 7.9) 573	CCL16, CCL2 (pIC50 9.3 – 10.2) 573,595,598,605,615, CCL13 (pIC50 8.6 – 8.7) 595,615, CCL7 (pIC50 8.4 – 8.7) 573,595,615, CCL11 (Partial agonist) (pIC50 7.1 – 7.7) 595,605	CCL28, CCL8, CCL7 (8.6 – 9.2) 575, CCL13 (pIC50 8.7 – 10.3) 599,615, CCL11 (Selective) (pIC50 8.7 – 9.0) 577,591,599,610,615, CCL24 (Selective) (pIC50 8.0 – 9.4) 599,605, CCL15 (pIC50 8.6) 573, CCL26 (Selective) (pIC50 7.9 – 8.9) 591,599,605	CCL22 (Selective) (pIC50 9.2) 589, CCL17 (Selective) (pIC50 8.7) 589	CCL16, CCL4 (Selective) (9.4 – 9.6) 602,609, CCL5 (9.2 – 9.7) 566,602,609, CCL8 (9.3) 609, CCL3 (8.0 – 8.9) 602,609,630, CCL2 (7.5) 602, CCL14 (7.2) 602, CCL11 (pIC50 7.7) 570
Selective agonists (pKi)	–	–	CCL11 {Sp: Mouse} (9.5 – 10.0) 575	–	R5-HIV-1 gp120
Non-selective agonists (pKi)	–	–	–	vMIP-III	–
Endogenous antagonists (pKi)	CCL4 (Selective) (7.1 – 7.8) 571,572	CCL26 (Selective) (pIC50 8.5) 605	CXCL10 (Selective), CXCL11 (CXCL11, O14625) (Selective), CXCL9 (Selective)	–	CCL7 (Selective) (7.5) 602
Selective antagonists (pKi)	CP-481,715 (pKd 8.0) 579, BX 471 (8.2 – 9.0) 593, 2b-1 (pIC50 8.7) 603, UCB35625 (pIC50 8.0) 610	GSK Compound 34 (7.6)	banyu (I) (Inverse agonist) (8.5) 617, SB328437 (8.4), BMS compound 87b (8.1) 616	–	MRK-1, vicriviroc (9.1) 613, aplaviroc (8.5) 596, ancriviroc (7.8 – 8.7) 596,604,613, TAK-779 (7.5) 596, E913 (pIC50 8.7) 597, maraviroc (pIC50 8.1) 602
Radioligands (Kd)	[125I]CCL7 (human) (Agonist, Full agonist) (7x10-10 M) 568, [125I]CCL3 (human) (Agonist, Full agonist) (1.58x10-9 – 1x10-8 M) 568,580,611, [125I]CCL5 (human) (Agonist, Full agonist) (7x10-9 M) 611	[125I]CCL2 (Agonist, Full agonist), [125I]CCL7 (human) (Agonist)	[125I]CCL5 (human) (Agonist), [125I]CCL7 (human) (Agonist), [125I]CCL11 (human) (Antagonist) (5.01x10-9 M) 617	[125I]CCL17 (Agonist, Full agonist), [125I]CCL27 (Agonist)	[125I]CCL3 (human) (Agonist), [125I]CCL5 (human) (Agonist), [125I]CCL8 (human) (Agonist), [125I]CCL4 (human) (Agonist, Full agonist) (2.51x10-10 M) 602
Comment	–	–	–	Monoclonal antibody mogamulizumab selectively blocks CCR4	–

Nomenclature	CCR6	CCR7	CCR8	CCR9	CCR10
HGNC, UniProt	CCR6, P51684	CCR7, P32248	CCR8, P51685	CCR9, P51686	CCR10, P46092
Principal transduction	Gi/o	Gi/o	Gi/o	Gi/o	Gi/o
Endogenous agonists (pKi)	beta-defensin 4A (DEFB4A, DEFB4B, O15263) (Selective) 625, CCL20 (pIC50 7.9 – 8.5) 564,565,606	CCL21 (Selective) (pIC50 9.3) 627, CCL19 (Selective) (pIC50 7.7 – 9.0) 626,627	CCL8 (Mouse), CCL1 (Selective) (pIC50 8.5 – 9.8) 574,585,590	CCL25 (Selective)	CCL27 (Selective), CCL28 (Selective)
Selective agonists (pKi)	–	–	vMIP-I (pIC50 8.9 – 9.9) 574,590	–	–
Selective antagonists (pKi)	–	–	vMCC-I (pIC50 9.4) 574	–	–
Radioligands (Kd)	[125I]CCL20 (Agonist, Full agonist) (∼1x10-10 M) 582	[125I]CCL19 (Agonist, Full agonist), [125I]CCL21 (Agonist, Full agonist)	[125I]CCL1 (human) (Agonist, Full agonist) (2.13x10-10 – 1.2x10-9 M) 590,608	[125I]CCL25 (Agonist, Full agonist)	–

Nomenclature	CXCR1	CXCR2	CXCR3	CXCR4	CXCR5	CXCR6
HGNC, UniProt	CXCR1, P25024	CXCR2, P25025	CXCR3, P49682	CXCR4, P61073	CXCR5, P32302	CXCR6, O00574
Principal transduction	Gi/o	Gi/o	Gi/o	Gi/o	Gi/o	Gi/o
Endogenous agonists (pKi)	CXCL8 (8.8 – 9.5) 569,584,592,622,623, CXCL6 (7.0) 624	CXCL6 (pKd 7.0) 624, CXCL8 (8.8 – 9.5) 569,584,592,622,623, CXCL1 (Selective) (8.4 – 9.7) 584,592,623, CXCL3 (Selective) (pIC50 7.8 – 9.2) 563, CXCL2 (Selective) (pIC50 7.0 – 9.1) 563, CXCL5 (Selective) (pIC50 6.9 – 9.0) 563, CXCL7 (Selective) (pIC50 6.3 – 9.3) 563	CXCL11 (Selective) (10.4 – 10.5) 586, CXCL10 (Selective) (7.8 – 9.8) 586,619, CXCL9 (Selective) (7.3 – 8.3) 586,619	SDF-1α (Selective) (pKd 7.7 – 8.2) 587,594, SDF-1β (Selective) (pKd 7.86) 587	CXCL13 (Selective)	CXCL16 (Selective) (pKd 9.0) 621
Endogenous antagonists (pKi)	–	–	CCL11 (Selective) (7.2) 619, CCL7 (Selective) (6.6) 619	–	–	–
Selective agonists (pKi)	–	–	–	X4-HIV-1 gp120, ALX40-4C (Partial agonist) (pIC50 6.1) 629	–	–
Non-selective agonists (pKi)	–	vCXCL-1	–	–	–	–
Selective antagonists (pKi)	–	SB 225002 (pIC50 7.7) 620	–	HIV-Tat, plerixafor (7.0) 629, T134 (pIC50 8.4) 614	–	–
Radioligands (Kd)	[125I]CXCL8 (human) (Agonist, Full agonist) (2.51x10-10 – 1.2x10-9 M) 584,607	[125I]CXCL1 (Agonist, Full agonist), [125I]CXCL5 (Agonist, Full agonist), [125I]CXCL7 (Agonist, Full agonist), [125I]CXCL8 (human) (Agonist, Full agonist) (3.98x10-10 – 1.02x10-9 M) 584,607	[125I]CXCL10 (Agonist, Full agonist), [125I]CXCL11 (Agonist, Full agonist)	[125I]SDF-1α (human) (Agonist, Full agonist) (3.98x10-9 – 7.94x10-9 M) 576,587	–	[125I]CXCL16 (Agonist, Full agonist)

Nomenclature	CX3CR1	XCR1	DARC
HGNC, UniProt	CX3CR1, P49238	XCR1, P46094	DARC, Q16570
Principal transduction	Gi/o	Gi/o	not defined
Endogenous agonists (pKi)	CX3CL1 (Selective) (pIC50 8.9) 578	XCL1 (Selective), XCL2 (Selective)	–
Endogenous ligands	–	–	CXCL5, CXCL6, CXCL8, CXCL11, CCL2, CCL5, CCL7, CCL11, CCL14, CCL17
Selective agonists (pKi)	–	SEAP-XCL1	–
Radioligands (Kd)	[125I]CX3CL1 (human) (Agonist, Full agonist)	–	–
Comment	–	When fused with secreted alkaline phophatase (SEAP), XCL1 functions as a probe at XCR1	–

Nomenclature	ACKR2	ACKR3	ACKR4	CCRL2
HGNC, UniProt	ACKR2, O00590	ACKR3, P25106	ACKR4, Q9NPB9	CCRL2, O00421
Principal transduction	arrestin	arrestin	not defined	not defined
Endogenous agonists (pKi)	–	CXCL11, SDF-1α (pEC50 7.52 – 7.9) 581,612	CCL19 (8.4) 618, CCL25 (7.6) 618, CCL21 (6.9) 618	–
Endogenous ligands	CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL13, CCL14, CCL17, CCL22	–	–	chemerin C-terminal peptide, CCL19 567

Comments

Mouse Cxcr binds iodinated mouse KC (CXCL1) and mouse MIP-2 (CXCL2) with high affinity (mouse KC and MIP-2 are homologues of human CXCL1 (CXCL1, P09341), CXCL2 (CXCL2, P19875) and CXCL3 (CXCL3, P19876)), but shows low affinity for human IL-8 (CXCL8 (IL8, P10145)).

Specific chemokine receptors facilitate cell entry by microbes, such as ACKR1 for Plasmodium vivax, and CCR5 for HIV-1. Virally encoded chemokine receptors are known (e.g. US28, a homologue of CCR1 from human cytomegalovirus and ORF74, which encodes a homolog of CXCR2 in Herpesvirus saimiri and Herpesvirus-68), but their role in viral life cycles is not established. Viruses can exploit or subvert the chemokine system by producing chemokine antagonists and scavengers.

The CC chemokine family (CCL1–28) includes I309 (CCL1 (CCL1, P22362)), MCP-1 (CCL2 (CCL2, P13500)), MIP-1α (CCL3 (CCL3, P10147)), MIP-1β (CCL4 (CCL4, P13236)), RANTES (CCL5 (CCL5, P13501)), MCP-3 (CCL7 (CCL7, P80098)), MCP-2 (CCL8 (CCL8, P80075)), eotaxin (CCL11 (CCL11, P51671)), MCP-4 (CCL13 (CCL13, Q99616)), HCC-1 (CCL14 (CCL14, Q16627)), Lkn-1/HCC-2 (CCL15 (CCL15, Q16663)), TARC (CCL17 (CCL17, Q92583)), ELC (CCL19 (CCL19, Q99731)), LARC (CCL20 (CCL20, P78556)), SLC (CCL21 (CCL21, O00585)), MDC (CCL22 (CCL22, O00626)), MPIF-1 (CCL23 (CCL23, P55773)), eotaxin-2 (CCL24 (CCL24, O00175)), TECK (CCL25 (CCL25, O15444)), eotaxin (CCL26 (CCL26, Q9Y258)), eskine/CTACK (CCL27 (CCL27, Q9Y4X3)) and MEC (CCL28 (CCL28, Q9NRJ3)). The CXC chemokine family (CXCL1–17) includes GROα (CXCL1 (CXCL1, P09341)), GROβ (CXCL2 (CXCL2, P19875)), GROγ (CXCL3 (CXCL3, P19876)), platelet factor 4 (CXCL4 (PF4, P02776)), ENA78 (CXCL5 (CXCL5, P42830)), GCP-2 (CXCL6 (CXCL6, P80162)), NAP-2 (CXCL7 (PPBP, P02775)), IL-8 (CXCL8 (IL8, P10145)), MIG (CXCL9 (CXCL9, Q07325)), IP10 (CXCL10 (CXCL10, P02778)), I-TAC (CXCL11 (CXCL11, O14625)), SDF-1 (CXCL12, i.e. SDF-1α (CXCL12, P48061) and SDF-1β (CXCL12, P48061)), BLC (CXCL13 (CXCL13, O43927)), BRAK (CXCL14 (CXCL14, O95715)), mouse lungkine (CXCL15) SR-PSOX (CXCL16 (CXCL16, Q9H2A7)) and CXCL17 (CXCL17, Q6UXB2). The CX₃C chemokine (CX3CL1 (CX3CL1, P78423)) is also known as fractalkine (neurotactin in the mouse). Like CXCL16 (CXCL16, Q9H2A7), and unlike other chemokines, CX3CL1 (CX3CL1, P78423) is multimodular containing a chemokine domain, an elongated mucin-like stalk, a transmembrane domain and a cytoplasmic tail. Both plasma membrane-associated and shed forms have been identified. The C chemokine (XCL1 (XCL1, P47992)) is also known as lymphotactin. Two chemokine receptor antagonists have now been approved by the FDA: the CCR5 antagonist maraviroc (Pfizer) for treatment of HIV/AIDS in patients with CCR5-using strains; and the CXCR4 antagonist plerixafor (Plerixifor, from Sanofi) for hematopoietic stem cell mobilization with G-CSF (CSF3, P09919) in patients undergoing transplantation in the context of chemotherapy for lymphoma and multiple myeloma.

Cholecystokinin receptors

Overview

Cholecystokinin receptors (nomenclature recommended by the NC-IUPHAR Subcommittee on CCK receptors, 644) are activated by the endogenous peptides cholecystokinin-4 (CCK-4 (CCK, P06307)), CCK-8 (CCK, P06307), CCK-33 (CCK, P06307) and gastrin (gastrin-17 (GAST, P01350)). There are only two distinct subtypes of CCK receptors, CCK₁ and CCK₂ receptors, with some alternatively spliced forms most often identified in neoplastic cells. The CCK receptor subtypes are distinguished by their peptide selectivity, with the CCK₁ receptor requiring the carboxyl-terminal heptapeptide-amide that includes a sulfated tyrosine for high affinity and potency, while the CCK₂ receptor requires only the carboxyl-terminal tetrapeptide shared by both CCK and gastrin peptides. These receptors have characteristic and distinct distributions, with both present in both the central nervous system and peripheral tissues.

Nomenclature	CCK1 receptor	CCK2 receptor
HGNC, UniProt	CCKAR, P32238	CCKBR, P32239
Principal transduction	Gq/11/Gs	Gs
Rank order of potency	CCK-8 >> gastrin-17, CCK-8 (desulphated) > CCK-4	CCK-8 ≥ gastrin-17, CCK-8 (desulphated), CCK-4
Endogenous agonists (pKi)	–	CCK-8 (desulphated) (pIC50 8.3 – 8.7) [14], CCK-4 (pIC50 7.5) 636
Selective agonists (pKi)	A-71623 (pIC50 8.4 - Rat) [2], JMV180 (pIC50 8.3) 639, GW-5823 (pIC50 7.6) 633	RB-400 (9.1 - Rat) [3], PBC-264 (pIC50 9.1 – Rat) 638, gastrin-17 (pIC50 8.3 - Mouse) 634
Selective antagonists (pKi)	devazepide (pIC50 9.7 - Rat) [8], T-0632 (pIC50 9.6 - Rat) 650, PD-140548 (pIC50 8.6 - Rat) 647, lintitript (pIC50 8.3) 632, lorglumide (pIC50 6.7 – 8.2 - Rat) 634,637	YF-476 (pIC50 9.7) [4,24], GV150013 (pIC50 9.4) 651, L-740093 (pIC50 9.2) 643, YM-022 (pIC50 9.2) 643, JNJ-26070109 (pIC50 8.5) 642, L-365260 (pIC50 8.4) 640, RP73870 (pIC50 8.0 - Rat) 641, LY262691 (pIC50 7.5 - Rat) 646
Radioligands(Kd)	[3H]devazepide (Antagonist) (2x10-10 M) [5]	[3H]L365260 (Antagonist) (2.9x10-9 – 5.7x10-9 M) [17], [3H]PD140376 (Antagonist) (Ki 1x10-10 – 2x10-10 M – Guinea pig) 635, [125I]PD142308 (Antagonist) (Ki 2.5x10-10 M), [125I]-BDZ2 (Antagonist) (Ki 3.98x10-9 M) 631, [125I]DTyr-Gly-[(Nle28,31)CCK-26-33 (Agonist, Full agonist) (IC50 1x10-9 M) 645, [125I]gastrin (Agonist, Full agonist) (IC50 1x10-9 M), [3H]gastrin (Agonist, Full agonist) (IC50 1x10-9 M)

Comments

While a cancer-specific CCK receptor has been postulated to exist, which also might be responsive to incompletely processed forms of CCK (Gly-extended forms), this has never been isolated. An alternatively spliced form of the CCK₂ receptor in which intron 4 is retained, adding 69 amino acids to the intracellular loop 3 (ICL3) region, has been described to be present particularly in certain neoplasms where mRNA mis-splicing has been commonly observed 648, but it is not clear that this receptor splice form plays a special role in carcinogenesis. Another alternative splicing event for the CCK₂ receptor was reported 649, with alternative donor sites in exon 4 resulting in long (452 amino acids) and short (447 amino acids) forms of the receptor differing by five residues in ICL3, however, no clear functional differences have been observed.

Complement peptide receptors

Formerly known as: Anaphylatoxin receptors

Overview

Complement peptide receptors (nomenclature as agreed by the NC-IUPHAR subcommittee on Complement peptide receptors, see 665) are activated by the endogenous ∼75 amino-acid anaphylatoxin polypeptides C3a (C3, P01024). C4a (C4A, P0C0L4) and C5a (C5, P01031), generated upon stimulation of the complement cascade.

Nomenclature	C3a receptor	C5a1 receptor	C5a2 receptor
HGNC, UniProt	C3AR1, Q16581	C5AR1, P21730	C5AR2, Q9P296
Principal transduction	Gi/o, Gz	Gi/o, Gz, G16 (Buhl et al., 1993)	–
Rank order of potency	C3a > C5a 653	C5a, C5a des-Arg (C5) > C3a 653	–
Endogenous agonists (pKi)	–	RP-S19 (RPS19, P39019) 675	–
Selective agonists (pKi)	E7 (pEC50 8.7) 654	N-methyl-Phe-Lys-Pro-D-Cha-Cha-D-Arg-CO2H (pIC50 7.6) 664,666	–
Selective antagonists (pKi)	SB290157 (pIC50 7.6) 652	CHIPS (pKd 9.0) 670, W54011 (8.7) 672, AcPhe-Orn-Pro-D-Cha-Trp-Arg (pIC50 7.9) 674, N-methyl-Phe-Lys-Pro-D-Cha-Trp-D-Arg-CO2H (pIC50 7.2) 666	–
Radioligands (Kd)	[125I]C3a (human) (Agonist, Full agonist) (3.85x10-9 M) 657	[125I]C5a (human) (Agonist, Full agonist) (2x10-9 M) 661	[125I]C5a (human) (Agonist, Full agonist)
Comment	–	–	Binds C5a complement factor, but appears to lack G protein signalling and has been termed a decoy receptor 671

Comments

SB290157 has also been reported to have agonist properties at the C3a receptor 668. The putative chemoattractant receptor termed C5a₂ (also known as GPR77, C5L2) binds [¹²⁵I]C5a with no clear signalling function, but has a putative role opposing inflammatory responses 656,658,659. Binding to this site may be displaced with the rank order C5a des-Arg (C5)> C5a (C5, P01031) 656,669 while there is controversy over the ability of C3a (C3, P01024) and C3a des Arg (C3, P01024) to compete 660,662,663,669. C5a₂ appears to lack G protein signalling and has been termed a decoy receptor 671. However, C5a₂ does recruit β-arrestin after ligand binding, which might provide a signaling pathway for this receptor 655,673. There are also reports of pro-inflammatory activity of C5a₂, mediated by HMGB1, but the signaling pathway that underlies this is currently unclear (reviewed in 667).

Corticotropin-releasing factor receptors

Overview

Corticotropin-releasing factor (CRF, nomenclature as recommended by the NC-IUPHAR sub-committee on Corticotropin-releasing Factor Receptors, 682) receptors are activated by the endogenous peptides CRF (CRH, P06850), a 41 amino-acid peptide, urocortin 1 (UCN, P55089), 40 amino-acids), urocortin 2 (UCN2, Q96RP3), 38 amino-acids) and urocortin 3 (UCN3, Q969E3), 38 amino-acids). CRF1 and CRF2 receptors are activated non-selectively by CRF (CRH, P06850) and urocortin 1 (UCN, P55089). Binding to CRF receptors can be conducted using [¹²⁵I]Tyr⁰-CRF or [125I]Tyr0-sauvagine with K^d values of 0.1–0.4 nM. CRF1 and CRF2 receptors are non-selectively antagonized by α-helical CRF, D-Phe-CRF-(12-41) and astressin.

Nomenclature	CRF1 receptor	CRF2 receptor
HGNC, UniProt	CRHR1, P34998	CRHR2, Q13324
Principal transduction	Gs	Gs
Endogenous agonists	–	urocortin 2 (Selective) (pKd 8.5 – 8.6) 679, urocortin 3 (Selective) (pKd 7.9 – 8.0) 679
Selective antagonists (pKi)	SSR125543A (8.7) 681, antalarmin (8.3 – 9.0) 688, DMP696 (8.3 – 9.0) 683, NBI27914 (8.3 – 9.0) 677, R121919 (8.3 – 9.0) 689, CP 154,526 (pIC50 9.3 – 10.4 - Rat) 685, CP376395 (pIC50 8.3 - Rat) 678, CRA1000 (pIC50 6.4 – 7.1) 676	antisauvagine (pKd 8.8 – 9.6) 680, K41498 (9.2) 684, K31440 (8.7 – 8.8) 687

Comments

A CRF binding protein has been identified (CRHBP, P24387) to which both CRF and urocortin 1 bind with high affinities, which has been suggested to bind and inactivate circulating CRF 686.

Dopamine receptors

Overview

Dopamine receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Dopamine Receptors, 723) are commonly divided into D₁-like (D₁ and D₅) and D₂-like (D₂, D₃ and D₄) families, where the endogenous agonist is dopamine.

Nomenclature	D1 receptor	D5 receptor	D2 receptor	D3 receptor	D4 receptor
HGNC, UniProt	DRD1, P21728	DRD5, P21918	DRD2, P14416	DRD3, P35462	DRD4, P21917
Principal transduction	Gs, Golf	Gs	Gi/o	Gi/o	Gi/o
(Sub)family-selective agonists (pKi)	A68930 (pEC50 6.82) 712	A68930 (pEC50 6.6) 712	quinpirole (4.9–7.7) 693,706,713,724,725,729	quinpirole (6.4–8.0) 693,706,710,713,724,725,729	quinpirole (7.5) 709,713,729
Selective agonists (pKi)	SKF-81297 (8.7 - Rat) 691, SKF-38393 (6.2–6.8) 726,727	–	sumanirole (8.1) 705	PD 128907 (7.6–7.7) 715,720	PD168,077 (Partial agonist) (8.8 - Rat) 700, A412997 (8.1 - Rat) 711
(Sub)family-selective antagonists (pKi)	SKF-83556 (9.5) 726, SCH-23390 (7.4–9.5) 726,727, ecopipam (8.3) 728	SKF-83556 (9.4) 726, SCH-23390 (7.5–9.5) 726, ecopipam (8.3) 726	haloperidol (7.4–8.8) 695,704,706,724,728	haloperidol (7.5–8.0) 695,724,728	haloperidol (8.7) 703,728
Selective antagonists (pKi)	–	–	L-741,626 (7.9–8.5) 696,701, domperidone (7.9–8.4) 695,724, raclopride (8.0) 710	S33084 (9.6) 708, nafadotride (9.52) 721, PG01037 (9.2) 697, NGB 2904 (8.8) 730, SB 277011-A (8.0) 716, (+)-S-14297 (7.9) 707	L745870 (9.4) 701, sonepiprazole (8.9) 722, L741742 (8.5) 719
(Sub)family-selective radioligands (Kd)	[3H]SCH-23390 (Antagonist) (3x10−10 M) 732	[3H]SCH-23390 (Antagonist) (5.8x10−10 M) 717	[3H]spiperone (Antagonist) (5.7x10−11 M - Rat) 692,699,731	–	[3H]spiperone (Antagonist) (3x10−10 M) 698,729
Radioligands (Kd)	[125I]SCH23982 (Antagonist) (3.5x10−10 M) 694	[125I]SCH23982 (Antagonist) (8x10−10 M)	[3H]raclopride (Antagonist) (1.2x10−9 M - Rat) 702	[3H]spiperone (Antagonist) (1.25x10−10 M - Rat) 699,731, [3H]7-OH-DPAT (Agonist) (2.7x10−10 M) 718, [3H]PD128907 (Agonist) (9.9x10−10 M) 690	[125I]L750667 (Antagonist) (1.6x10−10 M) 713, [3H]NGD941 (Antagonist) (5x10−9 M) 714
Comment	A68930 is an agonist with selectivity for D1-like receptors 712., SCH-23390 (pKi 9.5) 726, SKF-83556 (pKi 9.3) 726 and ecopipam (pKi 8.3) 728 are antagonists with selectivity for D1-like receptors	A68930 is an agonist with selectivity for D1-like receptors 712., SCH-23390 (pKi 9.5) 726, SKF-83556 (pKi 9.3) 726 and ecopipam (pKi 8.3) 728 are antagonists with selectivity for D1-like receptors	quinpirole is an agonist with selectivity for D2-like receptors 729	quinpirole is an agonist with selectivity for D2-like receptors 729	quinpirole is an agonist with selectivity for D2-like receptors 729

Comments

The selectivity of many of these agents is less than two orders of magnitude. [3H]raclopride exhibits similar high affinity for D₂ and D₃ receptors (low affinity for D₄), but has been used to label D₂ receptors in the presence of a D₃-selective antagonist. [3H]7-OH-DPAT has similar affinity for D₂ and D₃ receptors, but labels only D₃ receptors in the absence of divalent cations. The pharmacological profile of the D₅ receptor is similar to, yet distinct from, that of the D₁ receptor. The splice variants of the D₂ receptor are commonly termed D_2S and D_2L (short and long). The DRD4 gene encoding the D₄ receptor is highly polymorphic in humans, with allelic variations of the protein from amino acid 387 to 515.

Endothelin receptors

Overview

Endothelin receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on endothelin receptors, 736) are activated by the endogenous 21 amino-acid peptides endothelins 1–3 (ET-1 (EDN1, P05305), ET-2 (EDN2, P20800) and ET-3 (EDN3, P14138)).

Nomenclature	ETA receptor	ETB receptor
HGNC, UniProt	EDNRA, P25101	EDNRB, P24530
Principal transduction	Gq/11, Gs	Gq/11, Gi/o
Family selective agonists	ET-1 = ET-2 > ET-3 744	ET-1 = ET-2, ET-3
(Sub)family-selective antagonists (pKi)	TAK 044 (pA2 8.4 - Rat) 755, bosentan (pA2 7.2 - Rat) 735, SB209670 (pKB 9.4 - Rat) 739	–
Selective agonists (pKi)	–	sarafotoxin S6c (pKd 8.8–9.8) 743,752, [Ala1,3,11,15]ET-1 (pKd 8.7–9.2) 747, BQ 3020 (9.7) 751, IRL 1620 (8.7) 754
(Sub)family-selective antagonists (pKi)	–	TAK 044 (pA2 8.4 - Rat) 755, bosentan (pA2 6.0 - Rat) 735, SB209670 (pKB 9.4 - Rat) 739
Selective antagonists (pKi)	A127722 (pA2 9.2–10.5) 749, BQ123 (pA2 6.9–7.4) 744, ambrisentan (pA2 7.1) 733, PD-156707 (pKd 9.0–9.8) 745, FR139317 (Inverse agonist) (pIC50 7.3–7.9) 744	A192621 (pKd 8.1) 753, BQ788 (pKd 7.9–8.0) 752, IRL 2500 (pKd 7.2) 752, RO4868443 (pIC50 7.2) 734
Radioligands (Kd)	[125I]PD164333 (Antagonist) (1.58x10−10–2.5x10−10 M) 737, [3H]S0139 (Antagonist) (6x10−10 M), [125I]PD151242 (Antagonist) (7.9x10−10–1x10−9 M) 738, [3H]BQ123 (Antagonist) (3.2x10−9 M) 742	[125I]IRL1620 (Agonist, Full agonist) (7.9x10−11–1.26x10−10 M) 748, [125I][Ala1,3,11,15]ET-1 (Agonist, Full agonist) (2x10−10 M) 747, [125I]BQ3020 (Agonist, Full agonist) (1x10−10–5x10−9 M) 740,747,750

Comments

Splice variants of the ETA receptor have been identified in rat pituitary cells; one of these, ET_AR-C13, appeared to show loss of function with comparable plasma membrane expression 741. Subtypes of the ET_B receptor have been proposed, although gene disruption studies in mice suggest that the heterogeneity results from a single gene product 746.

Estrogen (G protein-coupled) receptor

Overview

The G protein-coupled estrogen receptor (GPER, provisional nomenclature) was identified following observations of estrogen-evoked cAMP signalling in breast cancer cells 756, which mirrored the differential expression of an orphan 7-transmembrane receptor GPR30 758. There are observations of both cell-surface and intracellular expression of the GPER receptor 763,764.

Nomenclature	HGNC, UniProt	Principal transduction	Selective agonists (pKi)	Selective antagonists (pKi)	Radioligands (Kd)
GPER	GPER1, Q99527	Gs 761, Gi/o 763	G-1 (8.0) 757	G36 (pIC50 6.78–6.95) 760, G15 (pIC50 6.7) 759	[3H]17β-estradiol (Agonist, Full agonist) (2.7x10−9–3.3x10−9 M) 764

Comments

Antagonists at the nuclear estrogen receptor, such as fulvestrant and tamoxifen 761, as well as the flavonoid ‘phytoestrogens’ genistein and quercetin 762, are agonists at GPER receptors.

Formylpeptide receptors

Overview

The formylpeptide receptors, nomenclature agreed by NC-IUPHAR Subcommittee on the formyl peptide receptor family, 787) respond to exogenous ligands such as the bacterial product fMet-Leu-Phe (fMLP) and endogenous ligands such as annexin I (ANXA1, P04083), cathepsin G (CTSG, P08311), amyloid β42, serum amyloid A and spinorphin, derived from β-haemoglobin (HBB, P68871).

Nomenclature	FPR1	FPR2/ALX	FPR3
HGNC, UniProt	FPR1, P21462	FPR2, P25090	FPR3, P25089
Principal transduction	Gi/o, Gz	Gi 778	–
Rank order of potency	fMet-Leu-Phe > cathepsin G (CTSG, P08311) > annexin I 776,783	LXA4=aspirin triggered lipoxin A4=ATLa2>LTC4=LTD4>>15-deoxy-LXA4>>fMet-Leu-Phe 765,766,768,770,784	–
Selective agonists (pKi)	fMet-Leu-Phe (pEC50 10.1–10.2) 769,782	–	–
Endogenous antagonists (pKi)	spinorphin (Selective) (pIC50 4.3) 777,780	aspirin triggered lipoxin A4 (Selective), LXA4 (Selective) (pEC50 ∼12.0) 775, resolvin D1 (Selective) (pEC50 ∼11.9) 775	–
Endogenous agonists(pKi)	F2L (HEBP1, Q9NRV9) (Selective) (pEC50 8.0–8.2) 779	–	–
Selective antagonists (pKi)	cyclosporin H (6.1–7.1) 785,786, t-Boc-FLFLF (6.0–6.5) 785	ATLa2 771	–
Radioligands (Kd)	[3H]fMet-Leu-Phe (Agonist, Full agonist) (5×10−10–2.51×10−8 M) 774	[3H]LXA4 (Agonist, Full agonist) (5×10−10–7×10−10 M) 766,767	–
Comment	A FITC-conjugated fMLP analogue has been used for binding to the mouse recombinant receptor 773	The agonist activity of the lipid mediators described has been questioned 772,781, which may derive from batch-to-batch differences, partial agonism or biased agonism	–

Comments

Note that the data for FPR2ALX are also reproduced on the leukotriene receptor page.

Free fatty acid receptors

Overview

Free fatty acid receptors (FFA, nomenclature as agreed by NC-IUPHAR Subcommittee on free fatty acid receptors, 792,814) are activated by free fatty acids. Long-chain saturated and unsaturated fatty acids (C14.0 (myristic acid), C16:0 (palmitic acid), C18:1 (oleic acid), C18:2 (linoleic acid), C18:3, (α-linolenic acid), C20:4 (arachidonic acid), C20:5,n-3 (EPA), C22:6,n-3 (docosahexaenoic acid)) activate FFA₁ 789,797,799 and FFA4 receptors 793,796,807, while short chain fatty acids (C2 (acetic acid), C3 (propanoic acid), C4 (butyric acid) and C5 (pentanoic acid)) activate FFA₂ 790,801,806 and FFA₃ 790,801 receptors. In addition, thiazolidinedione PPARγ agonists such as rosiglitazone activate FFA₁ (pEC₅₀ 5.2; 800,811,813) and small molecule allosteric modulators, such as 4-CMTB, have recently been characterised for FFA₂ 795,802,812.

Nomenclature	FFA1 receptor	FFA2 receptor	FFA3 receptor	FFA4 receptor
HGNC, UniProt	FFAR1, O14842	FFAR2, O15552	FFAR3, O14843	FFAR4, Q5NUL3
Principal transduction	Gq/11 789,797,809,813	Gq/11, Gi/o 790,801,806,808	Gi/o 790,801,808,813	Gq/11 793,807,810,819
Endogenous agonists (pKi)	docosahexaenoic acid (pEC50 5.4–6.0) 789,797	–	–	α-linolenic acid (pEC50 5.5) 810
(Sub)family-selective agonists (pKi)	α-linolenic acid (pEC50 4.6–5.7) 789,797,799, myristic acid (pEC50 4.5–5.1) 789,797,799, oleic acid (pEC50 3.9–5.7) 789,797,799	propanoic acid (pEC50 3.0–4.9) 790,801,806,808, acetic acid (pEC50 3.1–4.6) 790,801,806,808, trans-2-methylcrotonic acid (pEC50 3.8) 808, butyric acid (pEC50 2.9–4.6) 790,801,806,808, 1-methylcyclopropanecarboxylic acid (pEC50 2.6) 808	propanoic acid (pEC50 3.9–5.7) 790,801,808,820, butyric acid (pEC50 3.8–4.9) 790,801,808,820, 1-methylcyclopropanecarboxylic acid (pEC50 3.9) 808, acetic acid (pEC50 2.8–3.9) 790,801,808,820	myristic acid (pEC50 5.2) 819, oleic acid (pEC50 4.7) 819
Selective agonists (pKi)	AMG-837 (pEC50 8.5) 804, TUG-770 (pEC50 8.2) 791, GW9508 (pEC50 7.3) 788, TAK-875 (pEC50 7.1) 817, linoleic acid (pEC50 4.4–5.7) 789,797,799	3-benzyl-4-(cyclopropyl-(4-(2,5-dichlorophenyl)thiazol-2-yl)amino)-4-oxobutanoic acid (pEC50 7.1 - Rat) 794, (S)-4-CMTB (pEC50 6.4) 795,802	–	TUG-891 (pEC50 7.0) 810, NCG21 (pEC50 5.92) 816
Selective antagonists (pKi)	GW1100 (pIC50 6.0) 788	CATPB (pIC50 6.5) 795	–	–
Comment	Antagonist GW1100 has been shown to reduce [35S]GTPγS binding in FFAR1-expressing cells 813. GW1100 is also an oxytocin receptor antagonist 788. TUG770 and GW9508 are both approximately 100 fold selective for FFA1 over FFA4 788,791. AMG837 and the related analogue AM6331 have been suggested to have an allosteric mechanism of action at FFA1, with respect to the orthosteric fatty acid binding site 804,821	–	Beta-hydroxybutyrate has been reported to antagonise FFA3 responses to short chain fatty acids 798. trans-2-methylcrotonic acid is a weak agonist for FFA3, with a pEC of below 1 808	TUG891 exhibits 50–1000 fold selectivity for FFA4 over FFA1, dependent on the assay 810. NGC21 exhibits approximately 15 fold selectivity for FFA4 over FFA1 815

Comments

Short (361 amino acids) and long (377 amino acids) splice variants of human FFA4 have been reported 805, which differ by a 16 amino acid insertion in intracellular loop 3, and exhibit differences in intracellular signalling properties in recombinant systems 819. The long FFA4 splice variant has not been identified in other primates or rodents to date 793,805.

GPR42 was originally described as a pseudogene within the family (ENSFM00250000002583), but the recent discovery of several polymorphisms suggests that some versions of GPR42 may be functional 803. GPR84 is a structurally-unrelated G protein-coupled receptor which has been found to respond to medium chain fatty acids 818.

Frizzled Class GPCRs

Overview

Receptors of the Class Frizzled (FZD, nomenclature as agreed by the NC-IUPHAR subcommittee 832), are GPCRs originally identified in Drosophila 825, which are highly conserved across species. FZDs are activated by WNTs, which are cysteine-rich lipoglycoproteins with fundamental functions in ontogeny and tissue homeostatis. FZD signalling was initially divided into two pathways, being either dependent on the accumulation of the transcription regulator β-catenin (CTNNB1, P35222) or being β-catenin-independent (often referred to as canonical vs non-canonical WNT/FZD signalling, respectively). WNT stimulation of FZDs can, in cooperation with the low density lipoprotein receptors LRP5 (O75197) and LRP6 (O75581), lead to the inhibition of a constitutively active destruction complex, which results in the accumulation of β-catenin and subsequently its translocation to the nucleus. β-Catenin, in turn, modifies gene transcription by interacting with TCF/LEF transcription factors. β-Catenin-independent FZD signalling is far more complex with regard to the diversity of the activated pathways. WNT/FZD signalling can lead to the activation of pertussis toxin-sensitive heterotrimeric G proteins 830, the elevation of intracellular calcium 833, activation of cGMP-specific PDE6 822 and elevation of cAMP as well as RAC-1, JNK, Rho and Rho kinase signalling 828. Furthermore, the phosphoprotein Disheveled constitutes a key player in WNT/FZD signalling. As with other GPCRs, members of the Frizzled family are functionally dependent on the β-arrestin scaffolding protein for internalization 826, β-catenin-dependent 823 and -independent 824,831 signalling. The pattern of cell signalling is complicated by the presence of additional ligands, which can enhance or inhibit FZD signalling (secreted Frizzled-related proteins (sFRP), Wnt-inhibitory factor (WIF1, Q9Y5W5) (WIF), Sclerostin (SOST (SOST, Q9BQB4)) or Dickkopf (DKK)), as well as modulatory (co)-receptors with positive Ryk, ROR1, ROR2 and Kremen, which may also function as independent signalling proteins.

Nomenclature	FZD1	FZD2	FZD3	FZD4	FZD5	FZD6	FZD7	FZD8	FZD9	FZD10	SMO
HGNC, UniProt	FZD1, Q9UP38	FZD2, Q14332	FZD3, Q9NPG1	FZD4, Q9ULV1	FZD5, Q13467	FZD6, O60353	FZD7, O75084	FZD8, Q9H461	FZD9, O00144	FZD10, Q9ULW2	SMO, Q99835

Comments

There is limited knowledge about WNT/FZD specificity and which molecular entities determine the signalling outcome of a specific WNT/FZD pair. Understanding of the coupling to G proteins is incomplete (see 827). There is also a scarcity of information on basic pharmacological characteristics of FZDs, such as binding constants, ligand specificity or concentration–response relationships 829.

Ligands associated with FZD signalling

WNTs: Wnt-1 (WNT1, P04628), Wnt-2 (WNT2, P09544) (also known as Int-1-related protein), Wnt-2b (WNT2B, Q93097) (also known as WNT-13), Wnt-3 (WNT3, P56703), Wnt-3a (WNT3A, P56704), Wnt-4 (WNT4, P56705), Wnt-5a (WNT5A, P41221), Wnt-5b (WNT5B, Q9H1J7), Wnt-6 (WNT6, Q9Y6F9), Wnt-7a (WNT7A, O00755), Wnt-7b (WNT7B, P56706), Wnt-8a (WNT8A, Q9H1J5), Wnt-8b (WNT8B, Q93098), Wnt-9a (WNT9A, O14904) (also known as WNT-14), Wnt-9b (WNT9B, O14905) (also known as WNT-15 or WNT-14b), Wnt-10a (WNT10A, Q9GZT5), Wnt-10b (WNT10B, O00744) (also known as WNT-12), Wnt-11 (WNT11, O96014) and Wnt-16 (WNT16, Q9UBV4).

Extracellular proteins that interact with FZDs: norrin (NDP, Q00604), R-spondin-1 (RSPO1, Q2MKA7), R-spondin-2 (RSPO2, Q6UXX9), R-spondin-3 (RSPO3, Q9BXY4), R-spondin-4 (RSPO4, Q2I0M5), sFRP-1 (SFRP1, Q8N474), sFRP-2 (SFRP2, Q96HF1), sFRP-3 (FRZB, Q92765), sFRP-4 (SFRP4, Q6FHJ7), sFRP-5 (SFRP5, Q6FHJ7).

Extracellular proteins that interact with WNTs or LRPs: Dickkopf 1 (DKK1, O94907), WIF1 (Q9Y5W5), SOST (SOST, Q9BQB4), kremen 1 (KREMEN1, Q96MU8) and kremen 2 (KREMEN2, Q8NCW0)

Small exogenous ligands: Foxy-5, Box-5, UM206, and XWnt8 also known as mini-Wnt8.

GABAB receptors

Overview

Functional GABA_B receptors (nomenclature agreed by NC-IUPHAR Subcommittee on GABA_B receptors, 839,860) are formed from the heterodimerization of two similar 7TM subunits termed GABA_B1 (GABBR1, Q9UBS5) and GABA_B2 (GABBR2, O75899) 839,843,859,860,866. GABA_B receptors are widespread in the CNS and regulate both pre- and post-synaptic activity. The GABA_B1 subunit, when expressed alone, binds both antagonists and agonists, but the affinity of the latter is generally 10–100-fold less than for the native receptor. The GABA_B1 subunit when expressed alone is not transported to the cell membrane and is non-functional. Co-expression of GABA_B1 and GABA_B2 subunits allows transport of GABA_B1 to the cell surface and generates a functional receptor that can couple to signal transduction pathways such as high-voltage-activated Ca²⁺ channels (Ca_v2.1, Ca_v2.2), or inwardly rectifying potassium channels (Kir3) 837,839,840. The GABA_B2 subunit also determines the rate of internalisation of the dimeric GABA_B receptor 850. The GABA_B1 subunit harbours the GABA (orthosteric)-binding site within an extracellular domain (ECD) venus flytrap module (VTM), whereas the GABA_B2 subunit mediates G-protein-coupled signalling 839,849,859. The two subunits interact by direct allosteric coupling 857, such that GABA_B2 increases the affinity of GABA_B1 for agonists and reciprocally GABA_B1 facilitates the coupling of GABA_B2 to G proteins 855,859. GABA_B1 and GABA_B2 subunits assemble in a 1:1 stoichiometry by means of a coiled-coil interaction between α-helices within their carboxy-termini that masks an endoplasmic reticulum retention motif (RXRR) within the GABA_B1 subunit but other domains of the proteins also contribute to their heteromerization 837,859. Recent evidence indicates that higher order assemblies of GABA_B receptor comprising dimers of heterodimers occur in recombinant expression systems and in vivo and that such complexes exhibit negative functional cooperativity between heterodimers 841,858. Adding further complexity, KCTD (potassium channel tetramerization proteins) 8, 12, 12b and 16 associate as tetramers with the carboxy terminus of the GABA_B2 subunit to impart altered signalling kinetics and agonist potency to the receptor complex 835,864 and reviewed by 861. Four isoforms of the human GABA_B1 subunit have been cloned. The predominant GABA_B1(a) and GABA_B1(b) isoforms, which are most prevalent in neonatal and adult brain tissue respectively, differ in their ECD sequences as a result of the use of alternative transcription initiation sites. GABA_B1(a)-containing heterodimers localise to distal axons and mediate inhibition of glutamate release in the CA3–CA1 terminals, and GABA release onto the layer 5 pyramidal neurons, whereas GABA_B1(b)-containing receptors occur within dendritic spines and mediate slow postsynaptic inhibition 862,868. Isoforms generated by alternative splicing are GABA_B1(c) that differs in the ECD, and GABA_B1(e), which is a truncated protein that can heterodimerize with the GABA_B2 subunit but does not constitute a functional receptor. Only the 1a and 1b variants are identified as components of native receptors 839. Additional GABA_B1 subunit isoforms have been described in rodents and humans 856 and reviewed by 837.

Nomenclature	Principal transduction	Selective agonists (pKi)	Selective antagonists (pKi)	Radioligands (Kd)
GABAB receptor	Gi/o	3-APPA (5.2–7.2) 851, 3-APMPA (5.1) 869, CGP 44532 (pIC50 8.6 - Rat) 846, (-)-baclofen (pIC50 8.5 - Rat) 846	CGP 62349 (8.5–8.9) 851,869, CGP 55845 (7.8) 869, SCH 50911 (5.5–6.0) 851,869, CGP 35348 (4.4) 869, 2-hydroxy-saclofen (pIC50 4.1 - Rat) 853	[3H](R)-(-)-baclofen (Agonist), [3H]CGP 62349 (Antagonist) (9x10-10 M - Rat) 854, [125I]CGP 64213 (Antagonist) (1x10-9 M - Rat) 847, [125I]CGP 71872 (Antagonist) (1x10-9 M - Rat) 853, [3H]CGP 54626 (Antagonist) (Ki 7.9x10-10 M - Rat) 852

Comments

Potencies of agonists and antagonists listed in the table, quantified as IC₅₀ values for the inhibition of [3H]CGP27492 binding to rat cerebral cortex membranes, are from 839,845,846. Radioligand K_D values relate to binding to rat brain membranes. CGP 71872 is a photoaffinity ligand for the GABA_B1 subunit 836. CGP27492 (3-APPA), CGP35024 (3-APMPA) and CGP 44532 act as antagonists at human GABA_A ρ1 receptors, with potencies in the low micromolar range 845. In addition to the ligands listed in the table, Ca2+ binds to the VTM of the GABA_B1 subunit to act as a positive allosteric modulator of GABA 847. In cerebellar Purkinje neurones, the interaction of Ca2+ with the GABA_B receptor enhances the activity of mGlu₁, through functional cross-talk involving G-protein Gβγ subunits 863,865. Synthetic positive allosteric modulators with low, or no, intrinsic activity include CGP7930, GS39783, BHF-177 and (+)-BHFF 834,837,838,845. The site of action of CGP7930 and GS39783 appears to be on the heptahelical domain of the GABA_B2 subunit 842,859. In the presence of CGP7930, or GS39783, CGP 35348 and 2-hydroxy-saclofen behave as partial agonists 845. Knock-out of the GABA_B1 subunit in C57B mice causes the development of severe tonic-clonic convulsions that prove fatal within a month of birth, whereas GABA_B1^−/− BALB/c mice, although also displaying spontaneous epileptiform activity, are viable. The phenotype of the latter animals additionally includes hyperalgesia, hyperlocomotion (in a novel, but not familiar, environment), hyperdopaminergia, memory impairment and behaviours indicative of anxiety 844,867. A similar phenotype has been found for GABA_B2^−/− BALB/c mice 848.

Galanin receptors

Overview

Galanin receptors (provisional nomenclature, 876) are activated by the endogenous peptides galanin (GAL, P22466) and galanin-like peptide (GALP, Q9UBC7). Human galanin (GAL, P22466) is a 30 amino-acid non-amidated peptide 874; in other species, it is 29 amino acids long and C-terminally amidated. Amino acids 1–14 of galanin are highly conserved in mammals, birds, reptiles, amphibia and fish. Shorter peptide species (e.g. human galanin-1–19 872 and porcine galanin-5–29 885 and N-terminally extended forms (e.g. N-terminally seven and nine residue elongated forms of porcine galanin 873,885) have been reported.

Nomenclature	GAL1 receptor	GAL2 receptor	GAL3 receptor
HGNC, UniProt	GALR1, P47211	GALR2, O43603	GALR3, O60755
Principal transduction	Gi/o	Gi/o, Gq/11	Gi/o
Rank order of potency	galanin > galanin-like peptide 881	galanin-like peptide ≥ galanin 881	galanin-like peptide > galanin 878
Selective agonists (pKi)	–	[D-Trp2]galanin-(1–29) (8.15 - Rat) 887, galanin(2–29) (rat/mouse) (7.25–8.72 - Rat) 882,891–893	–
Selective antagonists (pKi)	2,3-dihydro-1,4-dithiin-1,1,4,4-tetroxide (pIC50 5.57) 884	M871 (7.88) 889	–

Comments

galanin-(1-11) is a high-affinity agonist at GAL₁/GAL₂ (pK_i 9), and galanin(2–11) is selective for GAL₂ and GAL₃ compared with GAL₁ 880. [¹²⁵I]-[Tyr²⁶]galanin binds to all three subtypes with K_d values ranging from 0.05 to 1 nM 875,886–888,892. Porcine galanin-(3–29) does not bind to cloned GAL₁, GAL₂ or GAL₃ receptors, but a receptor that is functionally activated by porcine galanin-(3–29) has been reported in pituitary and gastric smooth muscle cells 877,895. Additional galanin receptor subtypes are also suggested from studies with chimeric peptides (e.g. M15, M35 and M40), which act as antagonists in functional assays in the cardiovascular system 890, spinal cord 894, locus coeruleus, hippocampus 870 and hypothalamus 871,879, but exhibit agonist activity at some peripheral sites 871,877. The chimeric peptides M15, M32, M35, M40 and C7 are agonists at GAL₁ receptors expressed endogenously in Bowes human melanoma cells 881, and at heterologously expressed recombinant GAL₁, GAL₂ and GAL₃ receptors 875,887,888. Recent studies have described the synthesis of a series of novel, systemically-active, galanin analogues, with modest preferential binding at the GAL₂ receptor. Specific chemical modifications to the galanin backbone increased brain levels of these peptides after i.v. injection and several of these peptides exerted a potent antidepressant-like effect in mouse models of depression 883.

Ghrelin receptor

Overview

Ghrelin receptors (nomenclature approved by NC-IUPHAR, 898) are activated by a 28 amino-acid peptide originally isolated from rat stomach, where it is cleaved from a 117 amino-acid precursor (GHRL, Q9UBU3). The human gene encoding the precursor peptide has 83% sequence homology to rat prepro-ghrelin, although the mature peptides from rat and human differ by only two amino acids 907. Alternative splicing results in the formation of a second peptide, [des-Gln14]ghrelin (GHRL, Q9UBU3) with equipotent biological activity 904. A unique post-translational modification (octanoylation of Ser³, catalysed by ghrelin Ο-acyltransferase (MBOAT4, Q96T53) 913 occurs in both peptides, essential for full activity in binding to the ghrelin receptors in the hypothalamus and pituitary; and the release of growth hormone release from the pituitary 906. Structure activity studies showed the first five N-terminal amino acids to be the minimum required for binding 897, and receptor mutagenesis has indicated overlap of the ghrelin binding site with those for small molecule agonists and allosteric modulators of ghrelin (GHRL, Q9UBU3) function 902. In cell systems, the ghrelin receptor is constitutively active 903, but this is abolished by a naturally occurring mutation (A204E) that results in decreased cell surface receptor expression and is associated with familial short stature 910.

Nomenclature	HGNC, UniProt	Principal transduction	Rank order of potency	Selective antagonists (pKi)	Radioligands (Kd)
ghrelin receptor	GHSR, Q92847	Gq/11	ghrelin = [des-Gln14]ghrelin 896,907	GSK1614343 (pKB 8.0 - Rat) 911, YIL781 (pKB 8.0) 899, GSK1614343 (pIC50 8.4) 912	[125I][His9]ghrelin (human) (Agonist, Full agonist) (4x10-10 M) 905, [125I][Tyr4]ghrelin (human) (Agonist, Full agonist) (4x10-10 M) 909

Comments

[des-octanoyl]ghrelin has been shown to bind (as [125I]Tyr4-des-octanoyl-ghrelin) and have effects in the cardiovascular system 896, which raises the possible existence of different receptor subtypes in peripheral tissues and the central nervous system. A potent inverse agonist has been identified ([D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P, pD₂ 8.3; 901). TZP101, described as a ghrelin receptor agonist (pK_i 7.8 and pD₂ 7.5 at human recombinant ghrelin receptors), has been shown to stimulate ghrelin receptor mediated food intake and gastric emptying but not elicit release of growth hormone, or modify ghrelin stimulated growth hormone release, thus pharmacologically discriminating the orexigenic and gastrointestinal actions of ghrelin from the release of growth hormone 900. A number of selective antagonists have been reported, including peptidomimetic 908 and non-peptide small molecules including GSK1614343 911,912.

Glucagon receptor family

Overview

The glucagon family of receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on the Glucagon receptor family, 926) are activated by the endogenous peptide (27–44 aa) hormones glucagon, glucagon-like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), glucose-dependent insulinotropic polypeptide, also known as gastric inhibitory polypeptide or GIP (GIP, P09681), GHRH (GHRH, P01286) and secretin (SCT, P09683). One common precursor (GCG, P01275) generates glucagon, GLP-1 and GLP-2 peptides 922.

Nomenclature	glucagon receptor	GLP-1 receptor	GLP-2 receptor	GIP receptor	GHRH receptor	secretin receptor
HGNC, UniProt	GCGR, P47871	GLP1R, P43220	GLP2R, O95838	GIPR, P48546	GHRHR, Q02643	SCTR, P47872
Principal transduction	Gs	Gs	Gs	Gs	Gs	Gs
Endogenous agonists (pKi)	glucagon (Selective) (pEC50 9.0) 929	glucagon-like peptide-1-(7-37) (Selective) 919, glucagon-like peptide 1-(7-36) amide (Selective) (9.2) 923	GLP-2 (Selective) (pIC50 8.5) 932	GIP (Selective) (pKd 8.7) 938	–	secretin (Selective) (pEC50 9.7) 916
Selective agonists (pKi)	–	exendin-3 (P20394) 930, exendin-4 (8.7 – 9.0) 923	–	–	BIM28011 918, JI-38 (Rat) 924	–
Selective antagonists (pKi)	BAY27-9955 928, des-His1-[Glu9]glucagon-NH2 (pA2 7.2 - Rat) 934,935, NNC 92-1687 (5.0) 925, L-168,049 (pIC50 8.4) 915	exendin-(9-39) (8.1) 923, GLP-1-(9-36) (pIC50 6.91 - Rat) 927, T-0632 (pIC50 4.7) 933	–	[Pro3]GIP	JV-1-36 (10.1 – 10.4 - Rat) 931,936,937, JV-1-38 (10.1 - Rat) 931,936,937	[(CH2NH)4,5]secretin (5.3) 921
Radioligands (Kd)	[125I]glucagon (human, mouse, rat) (Agonist, Full agonist)	[125I]exendin, [125I]GLP-1-(7-37) (Agonist, Full agonist), [125I]GLP-1-(7-36)-amide (Agonist, Full agonist) (5x10-10 M) 923, [125I]exendin-(9-39) (Antagonist) (5x10-9 M) 923	–	[125I]GIP (Agonist, Full agonist) (2.51x10-9 M - Rat) 920	[125I]GHRH (human) (Agonist, Full agonist) (2.8x10-8 M - Rat) 914	[125I](Tyr10)secretin

Comments

The glucagon receptor has been reported to interact with receptor activity modifying proteins (RAMPs), specifically RAMP2, in heterologous expression systems 917, although the physiological significance of this has yet to be established.

Glycoprotein hormone receptors

Overview

Glycoprotein hormone receptors (provisional nomenclature) are activated by a non-covalent heterodimeric glycoprotein made up of a common α chain (glycoprotein hormone common alpha subunit (CGA, P01215) CGA, P01215), with a unique β chain that confers the biological specificity to FSH (CGA, FSHB, P01215, P01225), LH (LHB, CGA, P01229, P01215), hCG (CGA, CGB, P01233, P01215), CGB2/CGB or TSH (TSHB, CGA, P01222, P01215). There is binding cross-reactivity across the endogenous agonists for each of the glycoprotein hormone receptors. The deglycosylated hormones appear to exhibit reduced efficacy at these receptors 950.

Nomenclature	FSH receptor	LH receptor	TSH receptor
HGNC, UniProt	FSHR, P23945	LHCGR, P22888	TSHR, P16473
Principal transduction	Gs	Gs, Gq/11 and Gi	All four families of G proteins can be activated by this receptor
Endogenous agonists (pKi)	FSH (Selective)	hCG (Selective) (pKd 9.9 – 11.8) 942,946, LH (Selective) (pIC50 9.9 – 10.9) 942,946	TSH (Selective)
Radioligands (Kd)	[125I]FSH (human) (Agonist, Full agonist)	[125I]CG (human) (Agonist, Full agonist), [125I]LH (Agonist, Full agonist)	[125I]TSH (Agonist, Full agonist)
Comment	Animal follitropins are less potent than the human hormone as agonists at the human FSH receptor. Gain- and loss-of-function mutations of the FSH receptor are associated with human reproductive disorders 939–941,953. The rat FSH receptor also stimulates phosphoinositide turnover through an unidentified G protein 948.	Loss-of-function mutations of the LH receptor are associated with Leydig cell hypoplasia and gain-of-function mutations are associated with male-limited gonadotropin-independent precocious puberty (e.g. 944,951) and Leydig cell tumours 945.	Autoimmune antibodies that act as agonists of the TSH receptor are found in patients with Grave's disease (e.g. 949). Mutations of the TSH receptor exhibiting constitutive activity underlie hyperfunctioning thyroid adenomas 947 and congenital hyperthyroidism 943. TSH receptor loss-of-function mutations are associated with TSH resistance 952.

Gonadotrophin-releasing hormone receptors

Overview

GnRH₁ and GnRH₂ receptors (provisonal nomenclature, also called Type I and Type II, respectively) have been cloned from numerous species (most of which express two or three types of GnRH receptor) and grouped phylogenetically 975. Designated GnRH I (GNRH1, P01148) (to distinguish it from related peptides, such as GnRH II (GNRH2, O43555) (pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH₂, also known as chicken GnRH-II) is a hypothalamic decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pr-Gly-NH₂), also known as luteinising hormone-releasing hormone, gonadoliberin, luliberin, gonadorelin. Receptors for all three ligands exist in amphibians but only GnRH I (GNRH1, P01148) and GnRH II (GNRH2, O43555) (and their cognate receptors) have been found in mammals 969,974. GnRH₁ receptors are expressed primarily by pituitary gonadotrophs in mammals and mediate central control of reproduction. They are selectively activated by GnRH I (GNRH1, P01148) and all lack the C-terminal tails found in other GPCR. GnRH₂ receptors all possess C-terminal tails and (where tested) are selective for GnRH II (GNRH2, O43555) (over GnRH I (GNRH1, P01148)). An alternative phylogenetic classification 970 divided these receptors into three classes and includes both GnRH I-selective mammalian and GnRH II-selective non-mammalian receptors as GnRH₁ receptors. Although thousands of peptide analogues of GnRH I (GNRH1, P01148) have been synthesised and several (agonists and antagonists) are used therapeutically 961, the potency of most of these peptides at GnRH₂ receptors is unknown.

Nomenclature	GnRH receptor	GnRH2 receptor
HGNC, UniProt	GNRHR, P30968	GNRHR2, Q96P88
Principal transduction	Gq/11	Gq/11
Rank order of potency	GnRH I > GnRH II	GnRH II > GnRH I
Selective agonists (pKi)	buserelin, goserelin, histrelin, nafarelin, triptorelin (9.3 – 9.5) 954, leuprolide (8.5 – 9.1) 976	–
Selective antagonists (pKi)	ganirelix, abarelix (9.1 – 9.5) 976, antide (9.0) 972, cetrorelix (8.8) 972	trptorelix-1 967
Radioligands (Kd)	[125I]GnRH I (human, mouse, rat) (Agonist, Full agonist), [125I]buserelin (Agonist, Full agonist) (4x10-8 M - Rat) 964	[125I]GnRH II (human) (Agonist, Full agonist)

Comments

GnRH₁ and GnRH₂ receptors couple primarily to G_q/11 958 but coupling to G_s and G_i is evident in some systems 963. GnRH₂ receptors may also mediate (heterotrimeric) G protein-independent signalling to protein kinases 955. There is increasing evidence for expression of GnRH receptors on hormone-dependent cancer cells where they can exert antiproliferative and/or proapoptotic effects and mediate effects of cytotoxins conjugated to GnRH analogues 956,960,966,973. In some human cancer cell models GnRH II (GNRH2, O43555) is more potent than GnRH I (GNRH1, P01148), implying mediation by GnRH2 receptors 959. However, GnRH₂ receptors that are expressed by some primates are probably not expressed in humans because the human GNRHR₂ gene contains a frame shift and internal stop codon 971. The possibility remains that this gene generates GnRH₂ receptor-related proteins (other than the full-length receptor) that mediate responses to GnRH II (GNRH2, O43555) (see 972). Alternatively, there is evidence for multiple active GnRH receptor conformations 955,968,970 raising the possibility that GnRH₁ receptor-mediated proliferation inhibition in hormone-dependent cancer cells is dependent upon different conformations (with different ligand specificity) than effects on G_q/11 in pituitary cells 968. Loss-of-function mutations in the GnRH₁ receptor and deficiency of GnRH I (GNRH1, P01148) are associated with hypogonadotropic hypogonadism although some ‘loss of function’ mutations may actually prevent trafficking of ‘functional’ GnRH₁ receptors to the cell surface, as evidenced by recovery of function by nonpeptide antagonists 965. GnRH receptor signalling may be dependent upon receptor oligomerisation 957,962.

GPR18, GPR55 and GPR119

Overview

GPR18, GPR55 and GPR119 (provisional nomenclature), although showing little structural similarity to CB₁ and CB₂ cannabinoid receptors, respond to endogenous agents analogous to the endogenous cannabinoid ligands, as well as some natural/synthetic cannabinoid receptor ligands 988.

Nomenclature	GPR18	GPR55	GPR119
HGNC, UniProt	GPR18, Q14330	GPR55, Q9Y2T6	GPR119, Q8TDV5
Principal transduction	Gi/o 982	G12/13 989	Gs 984,987
Rank order of potency	–	–	N-oleoylethanolamide, N-palmitoylethanolamine > SEA (anandamide is ineffective) 987
Endogenous agonists (pKi)	N-arachidonoylglycine 982	2-arachidonoylglycerolphosphoinositol (Selective) 986, lysophosphatidylinositol (pEC50 5.5 – 7.3) 978,985,990	N-palmitoylethanolamine (Selective), SEA (Selective), N-oleoylethanolamide (Selective) (pEC50 5.4 – 6.3) 977,987,990
Selective agonists (pKi)	–	AM251 (pEC50 6.2 – 6.3) 978,980	AS1269574 (pEC50 5.6) 993, PSN632408 (pEC50 5.3) 987, PSN375963 (pEC50 5.1) 987
Comment	The pairing of N-arachidonoylglycine with GPR18 was not replicated in two studies based on β-arrestin assays 990,992	–	–

Comments

All listed endogenous agonists are remain currently as putative endogenous agonists.

GPR18 failed to respond to a variety of lipid-derived agents in an in vitro screen 992, but has been reported to be activated by Δ9-tetrahydrocannabinol 983. GPR55 responds to AM251 and rimonabant at micromolar concentrations, compared to their nanomolar affinity as CB₁ receptor antagonists/inverse agonists 988. It has been reported lysophosphatidylinositol acts at other sites 991. CID-16020046 has been described as a selective antagonist at GPR55 979,981, although it has not yet been fully characterized. It has also been suggested oleoyl-lysophosphatidylcholine acts, at least in part, through GPR119 984. Although PSN375963 and PSN632408 produce GPR119-dependent responses in heterologous expression systems, comparison with N-oleoylethanolamide-mediated responses suggests additional mechanisms of action 984.

Histamine receptors

Overview

Histamine receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Histamine Receptors, 1003) are activated by the endogenous ligand histamine. Marked species differences exist between histamine receptor orthologues (see 1003).

Nomenclature	H1 receptor	H2 receptor	H3 receptor	H4 receptor
HGNC, UniProt	HRH1, P35367	HRH2, P25021	HRH3, Q9Y5N1	HRH4, Q9H3N8
Principal transduction	Gq/11	Gs	Gi/o	Gi/o
Selective agonists (pKi)	methylhistaprodifen (6.4) 1025, histaprodifen (5.7) 1013	amthamine (pEC50 6.4) 1008	immethridine (9.1) 1007, methimepip (9.0) 1006	clobenpropit (Partial agonist) (7.4 – 8.3) 1000,1013–1015,1019, 4-methylhistamine (7.3 – 8.2) 1001,1013, VUF 8430 (7.5) 1012
Selective antagonists (pKi)	pyrilamine (Inverse agonist) (8.7 – 9.0) 995,1023, triprolidine (8.5 – 9.0) 995,1017	tiotidine (7.5 - Rat) 994, ranitidine (7.1) 1010	clobenpropit (8.4 – 9.4) 997,1000,1011,1014,1016,1028,1029, A331440 (8.5) 1002, iodophenpropit (8.2 – 8.7) 1028,1029, thioperamide (7.1 – 7.7) 997,999,1000,1011,1016,1028,1029	JNJ 7777120 (7.8 – 8.3) 1013,1026,1027
Radioligands (Kd)	[11C]pyrilamine, [11C]doxepin (Antagonist) (1x10-9 M) 1004, [3H]pyrilamine (Antagonist, Inverse agonist) (7.9x10-10 – 4x10-9 M) 998,1017,1024,1025	[125I]aminopotentidine (Antagonist) (2x10-9 M - Rat) 1009, [3H]tiotidine (Antagonist) (2.2x10-9 – 2x10-8 M) 1018	[123I]iodoproxyfan (Antagonist) (6.3x10-11 M) 1011, [125I]iodophenpropit (Antagonist) (6x10-10 M - Rat) 1005, [3H](R)-α-methylhistamine (Agonist, Full agonist) (6x10-10 M) 1014, N-[3H]α-methylhistamine (Agonist, Full agonist) (1x10-9 M - Mouse) 996	[3H]JNJ 7777120 (Antagonist) (3.6x10-9 M) 1027

Comments

histaprodifen and methylhistaprodifen are reduced efficacy agonists. The H₄ receptor appears to exhibit broadly similar pharmacology to the H₃ receptor for imidazole-containing ligands, although (R)-α-methylhistamine and N-α-methylhistamine are less potent, while clobenpropit acts as a reduced efficacy agonist 1014,1020–1022,1030. Moreover, 4-methylhistamine is identified as a high affinity, full agonist for the human H₄ receptor 1013. [3H]histamine has been used to label the H₄ receptor in heterologous expression systems.

Hydroxycarboxylic acid receptors

Formerly known as: Nicotinic acid receptor family

Overview

The hydroxycarboxylic acid family of receptors (ENSFM00500000271913, nomenclature as agreed by NC-IUPHAR Subcommittee on Hydroxycarboxylic acid receptors, 1037) respond to organic acids, including the endogenous hydroxy carboxylic acids 3-hydroxy butyric acid and L-lactic acid, as well as the lipid lowering agents nicotinic acid (niacin), acipimox and acifran 1040,1044,1045. These receptors were provisionally described as nicotinic acid receptors, although nicotinic acid shows submicromolar potency at HCA₂ receptors only and is unlikely to be the natural ligand 1044,1045.

Nomenclature	HCA1 receptor	HCA2 receptor	HCA3 receptor
HGNC, UniProt	HCAR1, Q9BXC0	HCAR2, Q8TDS4	HCAR3, P49019
Principal transduction	Gi/o 1031,1034,1036.	Gi/o 1040,1044,1045	Gi/o 1040,1045
Endogenous agonists (pKi)	L-lactic acid (Selective) (pEC50 1.3 – 2.89) 1032,1034,1036,1041	β-D-hydroxybutyric acid (pEC50 3.1) 1042	3-hydroxyoctanoic acid (pEC50 5.1) 1031
Selective agonists (pKi)	3,5-dihydroxybenzoic acid (pEC50 3.72) 1035	MK 6892 (pEC50 7.8) 1039, MK 1903 (pEC50 7.56) 1033, nicotinic acid (pEC50 6.0 – 7.2) 1040,1044,1045, acipimox (pEC50 5.2 – 5.6) 1040,1045, monomethylfumarate (pEC50 5.03) 1043	1-isopropylbenzotriazole-5-carboxylic acid (pEC50 6.4) 1038
Radioligands (Kd)	–	[3H]nicotinic acid (Agonist, Full agonist) (5.01x10-8 – 1x10-7 M) 1040,1044,1045	–

Comments

Further closely-related GPCR include the 5-oxoeicosanoid receptor (OXER1, Q8TDS5) and GPR31 (O00270).

Kisspeptin receptors

Overview

The kisspeptin receptor (nomenclature agreed by NC-IUPHAR committee on kisspeptin receptors, Kirby et al., 2010 1047), like neuropeptide FF (NPFF), prolactin-releasing peptide (PrP) and QRFP receptors (provisional nomenclature) responds to endogenous peptides with an arginine-phenylalanine-amide (RFamide) motif. kisspeptin-54 (KISS1, Q15726) (KP54, originally named metastin), kisspeptin-13 (KISS1, Q15726) (KP13) and kisspeptin-10 (KISS1) (KP10) are biologically-active peptides cleaved from the KISS1 (Q15726) gene product.

Nomenclature	HGNC, UniProt	Principal transduction	Endogenous agonists (pKi)	Selective agonists (pKi)	Selective antagonists (pKi)	Radioligands (Kd)
kisspeptin receptor	KISS1R, Q969F8	Gq/11 1048,1050	kisspeptin-10 (Selective) (8.6–10.4) 1048,1051, kisspeptin-54 (Selective) (8.8–9.5) 1048,1051, kisspeptin-13 (Selective) (8.4) 1048	4-fluorobenzoyl-FGLRW-NH2 (pEC50 9.2) 1053, [dY]1KP-10 (pIC50 8.4 - Mouse) 1046	peptide 234 1052	[125I]kisspeptin-14 (human) 1049, [125I]Tyr45-kisspeptin-15 (Agonist, Full agonist) (1 × 10−10 M) 1051, [125I]kisspeptin-13 (human) (Agonist, Full agonist) (2 × 10−10 M) 1049, [125I]kisspeptin-10 (human) (Agonist, Full agonist) (1.9 × 10−9 M) 1048

Leukotriene, lipoxin and oxoeicosanoid receptors

Overview

Leukotriene receptors (nomenclature agreed by NC-IUPHAR subcommittee on Leukotriene Receptors, 1057) are activated by the endogenous ligands leukotriene B₄ (LTB4), LTC4, LTD4, LTE4, 12R-HETE and 12S-HETE. CysLT₁ and CysLT₂ are co-expressed by most myeloid cells. However, the function of CysLT₂ remains unclear. CysLT₂ has been demonstrated to exert a suppressive influence on CysLT₁ expression, suggesting an autoregulatory function which is indicated by a reported up-regulation of CysLT-mediated responses in mice lacking CysLT₂ receptors 1073.

Leukotrienes bind extensively to enzymes in their metabolic pathways (glutathione-S-transferase/LTC₄ synthase, γ-glutamyltranspeptidase and several aminopeptidases) and can also bind to peroxisome proliferator-activated receptor α (PPARα, 1076) and the FPR2/ALX lipoxin receptor 1061, complicating the interpretation of radioligand binding and functional studies (e.g. LTC4 is rapidly converted in many systems to LTD4). Metabolic inhibitors (e.g. serine–borate complex) reduce this problem but can also have nonspecific effects.

Nomenclature	BLT1 receptor	BLT2 receptor	CysLT1 receptor	CysLT2 receptor
HGNC, UniProt	LTB4R, Q15722	LTB4R2, Q9NPC1	CYSLTR1, Q9Y271	CYSLTR2, Q9NS75
Principal transduction	Gq/11, Gi/o	Gq/11, Gi/o	Gq/11	Gq/11
Rank order of potency	LTB4 >20-hydroxy-LTB4 >>12R-HETE 1103	12-HHT > LTB4 > 12S-HETE = 12S-HPETE > 15S-HETE > 12R-HETE > 20-hydroxy-LTB4 1085,1103	LTD4 > LTC4 > LTE4 1077,1093	LTC4 ≥ LTD4 >> LTE4 1068,1082,1099
Endogenous agonists (pKi)	–	12S-HETE (Partial agonist) (pEC50<7.52) 1103	–	–
Selective antagonists (pKi)	U75302 (6.4) 1055, CP105696 (pIC50 8.1) 1095	LY255283 (pIC50 6.0–7.1) 1069,1103	ICI198615 (8.4–8.6), SR2640 (8.7), sulukast (8.3), zafirlukast (pIC50 8.59–8.74) 1077,1093, montelukast (pIC50 8.31–8.64) 1077,1093, pobilukast (pIC50 7.52) 1093	BAYu9773 (pA2 6.8–7.7 - Rat) 1100
Radioligands (Kd)	[3H]LTB4 (Agonist, Full agonist) (1.5×10−10 M) 1102, [3H]CGS23131 (Antagonist) (1.3×10−8 M) 1072	[3H]LTB4 (2×10−10 – 2.3×10−8 M)	[3H]ICI-198615 (Antagonist, in human lung parenchyma) (2.5×10−11 M) 1092, [3H]LTD4 (Agonist) (2×10−11 – 9.3×10−9 M)	[3H]LTD4 (Agonist, Full agonist, Kd1 and Kd-2 in COS-7 cells) (3.98×10−10 – 5.01×10−8 M) 1068

Nomenclature	FPR2/ALX	OXE receptor
HGNC, UniProt	FPR2, P25090	OXER1, Q8TDS5
Principal transduction	Gi 1078	Gi/o 1070,1071,1074,1083
Rank order of potency	LXA4=aspirin triggered lipoxin A4=ATLa2>LTC4=LTD4>>15-deoxy-LXA4>>fMet-Leu-Phe 1060,1061,1063,1065,1098	5-oxo-ETE, 5-oxo-C20:3, 5-oxo-ODE > 5-oxo-15-HETE > 5S-HPETE > 5S-HETE 1070,1074,1086
Endogenous agonists (pKi)	aspirin triggered lipoxin A4 (Selective), LXA4 (Selective) (pEC50 ∼12.0) 1075, resolvin D1 (Selective) (pEC50 ∼11.9) 1075	5-oxo-ETE (Selective) (pEC50 8.3–8.5) 1064,1084,1086,1089,1094
Selective antagonists (pKi)	ATLa2 1066	–
Radioligands (Kd)	[3H]LXA4 (Agonist, Full agonist) (5×10−10 – 7×10−10 M) 1061,1062	[3H]5-oxo-ETE (Agonist) (3.8×10−9 M) 1084
Comment	The agonist activity of the lipid mediators described has been questioned 1067,1088, which may derive from batch-to-batch differences, partial agonism or biased agonism.	–

Comments

BAYu9773 is an antagonist at CysLT₁ (6.8–7.7) and a reduced efficacy agonist at CysLT₂ receptors. The CysLT₁ and CyLT₂ receptors also respond to uracil nucleotides 1080,1081. GPR17 has been described as a ‘dualistic’ receptor responding to both uracil nucleotides and cysteinyl leukotrienes, responses which may be inhibited by antagonists of either P2 or CysLT receptors 1059.

Lipoxin A4 receptors (FPR2/ALX, nomenclature agreed by NC-IUPHAR on Leukotriene and Lipoxin Receptors; 1101) are activated by the endogenous lipid-derived, anti-inflammatory ligands lipoxin A₄ (LXA4) and 15-epi-LXA₄ (aspirin triggered lipoxin A4, ATL). The FPR2/ALX receptor also interacts with endogenous peptide and protein ligands, such as MHC binding peptide 1058 as well as annexin I (ANXA1, P04083) (ANXA1) and its N-terminal peptides 1087. In addition, a soluble hydrolytic product of protease action on the urokinase-type plasminogen activator receptor has been reported to activate the FPR2/ALX receptor 1090. Furthermore, FPR2/ALX has been suggested to act as a receptor mediating proinflammatory actions of the acute-phase reactant, serum amyloid A 1096,1097.

Oxoeicosanoid receptors (OXE, nomenclature agreed by NC-IUPHAR on Oxoeicosanoid Receptors; 1056) are activated by endogenous chemotactic eicosanoid ligands oxidised at the C-5 position, with 5-oxo-ETE the most potent agonist identified for this receptor.

Note that the data for FPR2/ALX are also reproduced on the Formylpeptide receptor pages. A receptor selective for LXB4 has been suggested from functional studies 1054,1079,1091. Initial characterization of the heterologously expressed OXE receptor suggested that polyunsaturated fatty acids, such as docosahexaenoic acid (DHA) and EPA, acted as receptor antagonists 1070.

Lysophospholipid (LPA) receptors

Overview

Lysophosphatidic acid (LPA) receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Lysophospholipid Receptors; 1104) are activated by the endogenous lipid derivative LPA. Originally identified as members of the endothelial differentiation gene (edg) family along with sphingosine 1-phosphate receptors, the gene names have recently been updated to LPAR1, etc. to reflect the receptor function of these proteins. The identified receptors can account for most, although not all, LPA-induced phenomena in the literature, indicating that a majority of LPA-dependent phenomena are receptor-mediated. Radioligand binding has been conducted in heterologous expression systems using [3H]LPA (e.g. 1107). In native systems, analysis of binding data is complicated by metabolism and high levels of nonspecific binding, and therefore the relationship between recombinant and endogenously expressed receptors is unclear. Targeted deletion of LPA receptors has clarified signalling pathways and identified physiological and pathophysiological roles. Independent validation by multiple groups has been reported in the peer-reviewed literature for all six LPA receptors described in the tables, including further validation using a distinct read-out via a novel TGFα “shedding” assay 1111. LPA has also been described to be an agonist at other orphan GPCRs (PSP24, GPR87 and GPR35), as well as at the nuclear hormone PPARγ receptors 1117,1119, although the physiological significance of these observations remain unclear.

Nomenclature	LPA1 receptor	LPA2 receptor	LPA3 receptor	LPA4 receptor	LPA5 receptor	LPA6 receptor
HGNC, UniProt	LPAR1, Q92633	LPAR2, Q9HBW0	LPAR3, Q9UBY5	LPAR4, Q99677	LPAR5, Q9H1C0	LPAR6, P43657
Principal transduction	Gi/o, Gq/11, G12/13	Gi/o, Gq/11, G12/13	Gi/o, Gq/11, Gs	Gi/o, Gq/11, Gs, G12/13 1115	Gq, G12/13 1114,1116	G12/13 1112,1122
Selective agonists (pKi)	–	dodecylphosphate (pEC50 6.2) 1121, decyl dihydrogen phosphate (pEC50 5.4) 1121, GRI977143 (pEC50 4.48) 1113	OMPT (pEC50 7.17) 1108	–	–	–
Selective antagonists (pKi)	AM966 (pIC50 7.8) 1120	H2L5186303 (7.68) 1105	dioctanoylglycerol pyrophosphate (5.5–7.0) 1106,1118	–	–	–

Comments

Ki16425 1118, dodecylphosphate 1121, VPC12249 1110 and VPC32179 1109 have antagonist activity at LPA₁ and LPA₃ receptors. The selectivity of these antagonists is less than two orders of magnitude. None of the currently available chemical tools have validated specificity in vivo.

Lysophospholipid (S1P) receptors

Overview

Sphingosine 1-phosphate (S1P) receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Lysophospholipid receptors; 1128) are activated by the endogenous lipid derivatives sphingosine 1-phosphate (S1P) and with lower apparent affinity, sphingosylphosphorylcholine (SPC). Originally identified as members of the endothelial differentiation gene (edg) family along with lysophosphatidic acid receptors, the gene names have been updated to S1PR1, etc. to reflect the receptor function of these proteins. Most cellular phenomena ascribed to S1P can be explained by receptor-mediated mechanisms; S1P has also been described to act at intracellular sites 1142, still awaiting precise definition. Previously-proposed SPC (or lysophophosphatidylcholine) receptors – G2A, TDAG8, OGR1 and GPR4 – are lacking confirmation of these roles 1130. The relationship between recombinant and endogenously expressed receptors is unclear. Radioligand binding has been conducted in heterologous expression systems using [32P]S1P (e.g 1137). In native systems, analysis of binding data is complicated by metabolism and high levels of nonspecific binding. Targeted deletion of several S1P receptors and key enzymes involved in S1P biosynthesis or degradation has clarified signalling pathways and physiological roles. A crystal structure of an S1P₁-T4 fusion protein has recently been described 1132.

Nomenclature	S1P1 receptor	S1P2 receptor	S1P3 receptor	S1P4 receptor	S1P5 receptor
HGNC, UniProt	S1PR1, P21453	S1PR2, O95136	S1PR3, Q99500	S1PR4, O95977	S1PR5, Q9H228
Principal transduction	Gi/o	Gq, G12/13, Gs	Gq, Gi/o, Gs	Gi/o, G12/13, Gs	Gi/o, G12/13
Rank order of potency	sphingosine 1-phosphate > dihydrosphingosine 1-phosphate > sphingosylphosphorylcholine 1124,1137	sphingosine 1-phosphate > dihydrosphingosine 1-phosphate > sphingosylphosphorylcholine 1124,1137	sphingosine 1-phosphate > dihydrosphingosine 1-phosphate > sphingosylphosphorylcholine 1137	sphingosine 1-phosphate > dihydrosphingosine 1-phosphate > sphingosylphosphorylcholine 1143	sphingosine 1-phosphate > dihydrosphingosine 1-phosphate > sphingosylphosphorylcholine 1133
Selective agonists (pKi)	SEW2871 (5.5 – 7.7) 1140, AUY954 (pEC50 8.92) 1139	–	–	–	–
Selective antagonists (pKi)	W146 (7.7) 1141	JTE-013 (pIC50 7.77) 1138	–	–	–

Comments

The immunomodulator fingolimod (FTY720) can be phosphorylated in vivo 1123 to generate a relatively potent agonist with activity at S1P₁, S1P₃, S1P₄ and S1P₅ receptors 1125,1134, although its biological activity appears to involve functional antagonism 1127,1129,1136. This compound has received world-wide approval as the first oral therapy for relapsing forms of Multiple Sclerosis, with a novel mechanism of action involving modulation of S1P receptors in both the immune and nervous systems 1126,1129,1131. VPC23019 and VPC44116 have antagonist activity at S1P₁ and S1P₃ receptors 1135.

Melanin-concentrating hormone receptors

Overview

Melanin-concentrating hormone (MCH) receptors (provisional nomenclature, 1148) are activated by an endogenous nonadecameric cyclic peptide identical in humans and rats (DFDMLRCMLGRVYRPCWQV) generated from a precursor (PMCH, P20382), which also produces neuropeptide EI and neuropeptide GE.

Nomenclature	MCH1 receptor	MCH2 receptor
HGNC, UniProt	MCHR1, Q99705	MCHR2, Q969V1
Principal transduction	Gq/11, Gi/o	Gq/11 1150–1152
Rank order of potency	melanin-concentrating hormone (human) > MCH (salmon)	melanin-concentrating hormone (human) = MCH (salmon) 1150
Selective antagonists (pKi)	SNAP-7941 (pA2 9.2) 1145, GW803430 (pIC50 9.3) 1149, T-226296 (pIC50 8.3) 1153, ATC0175 (pIC50 7.9–8.1) 1147	–
Radioligands (Kd)	[3H]MCH (human, mouse, rat) (Agonist, Full agonist) 1146, [125I]S36057 (Antagonist) (3.2x10−10–6.3x10−10 M) 1144, [125I][Phe13,Tyr19]MCH (Agonist, Full agonist) (7x10−10 M) 1146	–

Comments

The MCH₂ receptor appears to be a non-functional pseudogene in rodents 1154.

Melanocortin receptors

Overview

Melanocortin receptors (provisional nomenclature, 1158) are activated by members of the melanocortin family (α-MSH, β-MSH and γ-MSH derived from a common precursor, pro-opiomelanocortin (POMC, P01189) forms; – δ form is not found in mammals) and adrenocorticotrophin (ACTH (POMC, P01189)). Endogenous antagonists include agouti (ASIP, P42127) and agouti-related protein (AGRP (AGRP, O00253)).

Nomenclature	MC1 receptor	MC2 receptor	MC3 receptor	MC4 receptor	MC5 receptor
HGNC, UniProt	MC1R, Q01726	MC2R, Q01718	MC3R, P41968	MC4R, P32245	MC5R, P33032
Principal transduction	Gs	Gs	Gs	Gs	Gs
Rank order of potency	α-MSH > β-MSH > ACTH, γ-MSH	ACTH	γ-MSH, β-MSH > ACTH, α-MSH	β-MSH > α-MSH, ACTH > γ-MSH	α-MSH > β-MSH > ACTH > γ-MSH
Selective agonists (pKi)	–	–	[D-Trp8]γ-MSH (pIC50 8.2) 1159	MK-0493 1162, THIQ (pIC50 8.9) 1166	–
Selective antagonists (pKi)	–	–	PG-106 (pIC50 6.7) 1160	HS014 (8.5) 1165, MBP10 (pIC50 10.0) 1155	–
Radioligands (Kd)	[125I]NDP-MSH (Agonist, Full agonist) (3.3x10-10 M) 1161	[125I]ACTH-(1–24)	[125I]SHU9119 (Antagonist) 1163, [125I]NDP-MSH (Agonist, Full agonist) (2x10-10 M) 1161	[125I]SHU9119 (Antagonist) (7x10-10 M) 1163, [125I]NDP-MSH (Agonist, Full agonist) (1.2x10-9–4x10-9 M) 1161,1164	[125I]NDP-MSH (Agonist, Full agonist) (2.8x10-9 M) 1161

Comments

Polymorphisms of the MC1 receptor have been linked to variations in skin pigmentation. Defects of the MC2 receptor underlie familial glucocorticoid deficiency. Polymorphisms of the MC4 receptor have been linked to obesity 1156,1157.

Melatonin receptors

Overview

Melatonin receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on melatonin receptors, 1170) are activated by the endogenous ligands melatonin and N-acetylserotonin.

Nomenclature	MT1 receptor	MT2 receptor
HGNC, UniProt	MTNR1A, P48039	MTNR1B, P49286
Principal transduction	Gi/o	Gi/o
Selective agonists (pKi)	–	5-methoxy-luzindole (Partial agonist) (9.6) 1171, IIK7 (pIC50 10.3) 1183
Selective antagonists (pKi)	–	K185 (9.3) 1175,1183, 4P-PDOT (8.8–9.3) 1167,1171, DH97 (8.0) 1184
Radioligands (Kd)	2-[125I]MLT (Agonist, Full agonist) (2.13×10−11 – 1.19×10−10 M) 1167,1171, [3H]melatonin (Agonist, Full agonist) (1.3×10−10 – 4×10−10 M) 1169	2-[125I]MLT (Agonist, Full agonist) (1.07×10−10 – 1.86×10−10 M) 1167,1171, [3H]melatonin (Agonist, Full agonist) (2.8×10−10 – 9.12×10−10 M) 1169

Comments

melatonin, 2-iodo-melatonin, S20098 (agomelatine), GR 196429, LY 156735 and ramelteon 1176 are nonselective agonists for MT₁ and MT₂ receptors. (-)-AMMTC displays an ∼400-fold greater agonist potency than (+)-AMMTC at rat MT₁ receptors (see AMMTC for structure) 1185. luzindole is an MT₁/MT₂ melatonin receptor-selective competitive antagonist with some selectivity for the MT2 receptor 1172. MT₁/MT₂ heterodimers present different pharmacological profiles from MT₁ and MT₂ receptors 1168.

The MT₃ binding site of hamster brain and peripheral tissues such as kidney and testis, also termed the ML₂ receptor, binds selectively 2-iodo-[125I]5MCA-NAT 1178. Pharmacological investigations of MT₃ binding sites have primarily been conducted in hamster tissues. At this site, N-acetylserotonin 1174,1177,1178,1182 and 5MCA-NAT 1182 appear to function as agonists, while prazosin 1177 functions as an antagonist. A suggested physiological function of the MT₃ receptor is in the control of intraocular pressure in rabbits 1181. The MT₃ binding site of hamster kidney was also identified as the hamster homologue of human quinone reductase 2 (NQO2, P16083 1179,1180). Xenopus melanophores and chick brain express a distinct receptor (x420, P49219; c346, P49288, initially termed Mel_1C) coupled to the G_i/o family of G proteins, for which GPR50 has recently been suggested to be a mammalian counterpart 1173 although melatonin does not bind to GPR50 receptors.

Metabotropic glutamate receptors

Overview

Metabotropic glutamate (mGlu) receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Metabotropic Glutamate Receptors, 1243) are activated by the endogenous ligands L-glutamic acid, L-serine-O-phosphate (L-SOP), N-acetylaspartylglutamate (NAAG) and L-cysteine sulphinic acid. Examples of agonists selective for mGlu receptors compared with ionotropic glutamate receptors are (1S,3R)-ACPD and L-CCG-I, which show limited selectivity for Group II receptors. An example of an antagonist selective for mGlu receptors is LY341495, which blocks mGlu₂ and mGlu₃ at low nanomolar concentrations, mGlu₈ at high nanomolar concentrations, and mGlu₃, mGlu₄, mGlu₅ and mGlu₇ in the micromolar range 1210. Three groups of native receptors are distinguishable on the bases of similarities of agonist pharmacology, primary sequence and G-protein effector coupling: Group I (mGlu₁ and mGlu₅), Group II (mGlu₂ and mGlu₃) and Group III (mGlu₄, mGlu₆, mGlu₇ and mGlu₈) (see Further reading). Group I mGlu receptors may be activated by 3,5-DHPG and (S)-3HPG 1190 and antagonized by (S)-hexylhomoibotenic acid 1221. Group II mGlu receptors may be activated by LY389795 1229, LY379268 1229, LY354740 1244,1254, DCG-IV and (2R,3R)-APDC 1245, and antagonised by eGlu (4.3, 1207 and LY307452 1200,1253. Group III mGlu receptors may be activated by (R,S)-4-PPG 1203.

In addition to orthosteric ligands that directly interact with the glutamate recognition site directly, allosteric modulators have been described. Negative allosteric modulators are listed separately. The positive allosteric modulators most often act as ‘potentiators’ of an orthosteric agonist response, without significantly activating the receptor in the absence of agonist.

Nomenclature	mGlu1 receptor	mGlu5 receptor
HGNC, UniProt	GRM1, Q13255	GRM5, P41594
Principal transduction	Gq/11	Gq/11
Selective agonists (pKi)	–	(S)-(+)-CBPG (Partial agonist) (pEC50 4.3 - Rat) 1225, CHPG (pIC50 3.4) 1232
Selective antagonists (pKi)	AIDA (pA2 4.2) 1231, 3-MATIDA (pIC50 5.2-Rat) 1230, LY367385 (pIC50 5.1) 1196, (S)-(+)-CBPG (pIC50 4.2-Rat) 1225, (S)-TBPG (pIC50 4.2-Rat) 1197	ACDPP (pIC50 6.9) 1188
Selective allosteric regulators	PHCCC (Positive), Ro67-7476 (Positive) (pKi 7.5–7.9 - Rat) 1213, Ro01-6128 (Positive) (pKi 7.5–7.7 - Rat) 1213, Ro67-4853 (Positive) (pKi 5.1 - Rat) 1213, JNJ16259685 (Negative) (pIC50 8.9) 1217, A-841720 (Negative) (pIC50 8.0) 1255, 3,5-dimethyl PPP (Negative) (pIC50 7.8-Rat) 1227, YM298198 (Negative) (pIC50 7.8-Rat) 1214, BAY 367620 (Negative) (pIC50 6.8–8.0-Rat) 1193,1216, EM-TBPC (Negative) (pIC50 6.9-Rat) 1223, LY456236 (Negative) (pIC50 6.9) 1218, CPCCOEt (Negative) (pIC50 5.2–5.8) 1220	MTEP (Negative) (pKi 7.8) 1191, VU-1545 (Positive) (pEC50 8.0) 1198, CDPPB (Positive) (pEC50 7.6–8.0) 1211,1219, MPEP (Negative) (pIC50 7.4–7.7) 1202,1204, fenobam (Negative) (pIC50 7.2) 1241, DFB (Positive) (pIC50 5.6–8.5) 1236,1237, CPPHA (Positive) (pIC50 6.3) 1237, SIB-1757 (Negative) (pIC50 6.0–6.4) 1202,1252, SIB-1893 (Negative) (pIC50 5.9–6.5) 1202,1252

Nomenclature	mGlu2 receptor	mGlu3 receptor
HGNC, UniProt	GRM2, Q14416	GRM3, Q14832
Principal transduction	Gi/o	Gi/o
Selective antagonists (pKi)	PCCG-4 (pIC50 5.1 - Rat) 1239	–
Selective allosteric regulators	biphenylindanone A (Positive) (pEC50 7.0) 1189, CBiPES (Positive) (pEC50 7.0) 1209, Ro64-5229 (Negative) (pIC50 7.0 - Rat) 1215, 4-MPPTS (Positive) (pIC50 5.8) 1187,1208,1209,1242	–
Endogenous agonists (pKi)	–	NAAG (Selective) (4.7) 1246

Nomenclature	mGlu4 receptor	mGlu6 receptor	mGlu7 receptor	mGlu8 receptor
HGNC, UniProt	GRM4, Q14833	GRM6, O15303	GRM7, Q14831	GRM8, O00222
Principal transduction	Gi/o	Gi/o	Gi/o	Gi/o
Endogenous agonists (pKi)	–	–	–	L-SOP (pIC50 6.2–7.2) 1224,1254
Non-selective agonists (pKi)	L-AP4 (pEC50 6.5) 1254, L-SOP (pEC50 5.9) 1254	–	L-SOP (pEC50 4.5) 1254, L-AP4 (pEC50 3.8) 1254	L-AP4 (pIC50 7.0–7.2) 1224
Selective agonists (pKi)	LSP4-2022 1205	1-benzyl-APDC (pEC50 4.7 - Rat) 1250, homo-AMPA (pEC50 4.1) 1192	LSP4-2022 (pEC50 4.96) 1205	(S)-3,4-DCPG (pEC50 7.5) 1248
Non-selective antagonists (pKi)	MAP4 (4.6 - Rat) 1206	MAP4 (pIC50 3.5 - Rat) 1240	–	MPPG (pIC50 4.33) 1254
Selective antagonists (pKi)	–	THPG 1249	–	–
Non-selective allosteric regulators	SIB-1893 (Positive) (pEC50 6.3–6.8) 1226, MPEP (Positive) (pEC50 6.3–6.6) 1226, PHCCC (Positive) (pEC50 4.5) 1222	–	AMN082 (Positive) (pEC50 6.5–6.8) 1228	–
Selective allosteric regulators	VU0361737 (Positive) (pEC50 6.6) 1199, VU0155041 (Positive) (pEC50 6.1) 1235	–	MMPIP (Negative) (pIC50 6.1–7.6 - Rat) 1234,1247	–
Comment	pEC50 values for MPEP and SIB-1893 were obtained in the presence of L-AP4 1226	–	–	–

Comments

The activity of NAAG as an agonist at mGlu₃ receptors was questioned on the basis of contamination with glutamate 1194,1201, but this has been refuted 1233.

Radioligand binding using a variety of radioligands has been conducted on recombinant receptors (for example, [3H]R214127 1216 and [3H]YM298198 1214 at mGlu₁ receptors and [3H]M-MPEP 1202 and [3H]methoxymethyl-MTEP 1186 at mGlu₅ receptors. Although a number of radioligands have been used to examine binding using native tissues, correlation with individual subtypes is limited. Many pharmacological agents have not been fully tested across all known subtypes of mGlu receptors. Potential differences linked to the species (e.g. human versus rat or mouse) of the receptors and the receptor splice variants are generally not known. The influence of receptor expression level on pharmacology and selectivity has not been controlled for in most studies, particularly those involving functional assays of receptor coupling.

(S)-(+)-CBPG is an antagonist at mGlu₁, but is an agonist (albeit of reduced efficacy) at mGlu₅ receptors. DCG-IV also exhibits agonist activity at NMDA glutamate receptors 1251, and is an antagonist at all group-III mGluRs with an IC50 of 30μM. A potential novel metabotrophic glutamate receptor coupled to phosphoinositide turnover has been observed in rat brain; it is activated by 4-methylhomoibotenic acid (ineffective as an agonist at recombinant Group I metabotrophic glutamate receptors), but resistant to LY341495 1195. There are also reports of a distinct metabotrophic glutamate receptor coupled to phospholipase D in rat brain, which does not readily fit into the current classification 1212,1238.

A related class C receptor composed of two distinct subunits, T1R1 +T1R3 is also activated by glutamate and is responsible for umùami taste detection.

All selective antagonists at metabotropic glutamate receptors are competitive.

Motilin receptor

Overview

Motilin receptors (provisional nomenclature, 1261) are activated by a 22 amino-acid peptide derived from a precursor (MLN, P12872), which may also generate a motilin-associated peptide (MLN, P12872). These receptors are also suggested to be responsible for the gastrointestinal prokinetic effects of certain macrolide antibiotics (often called motilides; e.g. erythromycin), although for many of these molecules the evidence is sparse.

Nomenclature	HGNC, UniProt	Principal transduction	Endogenous agonists (pKi)	Selective agonists (pKi)	Selective antagonists (pKi)	Radioligands (Kd)	Comment
motilin receptor	MLNR, O43193	Gq/111259,1260	motilin (8.4 – 8.7) 1258,1265–1267	GSK962040 (pEC50 7.9) 1275, mitemcinal (pEC50 7.5 – 7.8 - Rabbit) 1263,1273, azithromycin (pEC50 5.5) 1256, mitemcinal (pIC50 8.1 – 8.2 - Rabbit) 1257, ABT-229 (pIC50 7.2) 1274, erythromycin-A (pIC50 5.5 – 6.5) 1260,1274	MA-2029 (pA2 9.2) 1271, GM-109 (pA2 7.2 – 7.5 - Rabbit) 1257,1272, GM-109 (pIC50 8.0 - Pig) 1262	[125I]motilin (human) (Agonist, Full agonist) (1x10-10 M) 1260	Note that for the complex macrolide structures, selectivity of action has often not been rigorously examined and other actions are possible (e.g. P2X inhibition by erythromycin; 1277). Small molecule motilin receptor agonists are now described 1264,1270,1276.

Comments

In laboratory rodents, the gene encoding the motilin percursor appears to be absent, while the receptor appears to be a pseudogene. Functions of motilin (MLN, P12872) are not usually detected in rodents, although brain and other responses to motilin (MLN, P12872) and the macrolide ABT-229 have been reported and the mechanism of these actions are obscure 1268,1269.

Neuromedin U receptors

Overview

Neuromedin U receptors (provisional nomenclature, 1279) are activated by the endogenous 25 amino acid peptide neuromedin U (NMU-25 (NMU, P48645), NMU), a peptide originally isolated from pig spinal cord 1285. In humans, NMU-25 appears to be the sole product of a precursor gene (NMU, P48645) showing a broad tissue distribution, but which is expressed at highest levels in the upper gastrointestinal tract, CNS, bone marrow and fetal liver. Much shorter versions of NMU are found in some species, but not in human, and are derived at least in some instances from the proteolytic cleavage of the longer NMU. Despite species differences in NMU structure, the C-terminal region (particularly the C-terminal pentapeptide) is highly conserved and contains biological activity. Neuromedin S (NMS-33 (NMS, Q5H8A3)) has also been identified as an endogenous agonist 1286. NMS-33 is, as its name suggests, a 33 amino-acid product of a precursor protein derived from a single gene and contains an amidated C-terminal heptapeptide identical to NMU. NMS-33 appears to activate NMU receptors with equivalent potency to NMU-25.

Nomenclature	NMU1 receptor	NMU2 receptor
HGNC, UniProt	NMUR1, Q9HB89	NMUR2, Q9GZQ4
Principal transduction	Gq/11 1278,1280	Gq/11 1278,1281
Selective antagonists (pKi)	–	R-PSOP (pKB 7.04) 1283

Comments

NMU1 and NMU2 couple predominantly to G_q/11 although there is evidence of good coupling to G_i/o 1278,1281,1282. NMU1 and NMU2 can be labelled with [¹²⁵I]-NMU and [¹²⁵I]-NMS (of various species, e.g. 1284), BODIPY® TMR-NMU or Cy3B-NMU-8 1278. A range of radiolabelled (¹²⁵I-), fluorescently labelled (e.g. Cy3, Cy5, rhodamine and FAM) and biotin labelled versions of NMU-25 (NMU, P48645) and NMS-33 (NMS, Q5H8A3) are now commercially available.

Neuropeptide FF/neuropeptide AF receptors

Overview

A single propeptide precursor (NPFF, O15130) generates the octapeptides NPFF (FLFQPQRF-NH₂, neuropeptide FF or F-8-F-amide) and NPSF (SLAAPQRF-NH₂, neuropeptide SF) and the octadecapeptide NPAF (AGEGLSSPFWSLAAPQRF-NH₂, neuropeptide AF or A-18-F-amide). NPFF and NPAF were originally isolated from bovine brain 1298.

Nomenclature	NPFF1 receptor	NPFF2 receptor
HGNC, UniProt	NPFFR1, Q9GZQ6	NPFFR2, Q9Y5X5
Principal transduction	Gq/11	Gi/o 1293
Rank order of potency	FMRF, NPFF > NPAF > NPSF, QRFP, PrRP-31 (PRLH) 1287	NPAF, NPFF > PrRP-31 (PRLH) > FMRF, QRFP (QRFP, P83859) > NPSF 1287
Endogenous agonists (pKi)	RFRP-3 (NPVF, Q9HCQ7) (Selective) (9.2 – 9.3) 1288,1289,1292, NPFF (NPFF, O15130) (Selective) (8.5 – 9.9) 1287,1288,1292	NPFF (Selective) (9.7) 1288,1291
Selective agonists (pKi)	–	dNPA (10.6) 1294,1295, AC263093 (pEC50 5.2 – 5.9) 1290
Selective antagonists (pKi)	AC262620 (7.7 – 8.1) 1290, AC262970 (7.4 – 8.1) 1290, RF9 (7.2) 1296	–
Radioligands (Kd)	[125I]NPFF (Agonist, Full agonist) 1287, [125I]Y-RFRP-3 (Agonist, Full agonist) (8x10-9 M) 1288, [3H]NPVF (Agonist, Full agonist) (2.65x10-9 M) 1297	[125I]NPFF (Agonist, Full agonist) 1287, [125I]EYF (Agonist, Full agonist) (6.3x10-11 M) 1292, [3H]EYF (Agonist, Full agonist) (5.4x10-10 M) 1297

Comments

An orphan receptor GPR83 (Q9NYM4) shows sequence similarities with NPFF1, NPFF2, PrRP and QRFP receptors. The antagonist RF9 is selective for NPFF receptors, but does not distinguish between the NPFF1 and NPFF2 subtypes (pK_i 7.1 and 7.2, respectively, 1296).

Neuropeptide S receptor

Overview

The neuropeptide S receptor (NPS, provisional nomenclature, 1300) responds to the 20 amino-acid peptide neuropeptide S derived from the precursor (NPS, P0C0P6).

Nomenclature	HGNC, UniProt	Principal transduction	Endogenous agonists (pKi)	Radioligands (Kd)
NPS receptor	NPSR1, Q6W5P4	Gs, Gq/11 1301,1302	NPS (pEC50 8.0) 1303	[125I]Tyr10NPS (human) (Agonist, Full agonist) (3.3x10−10 M) 1303

Comments

Polymorphisms in the NPS receptor have been suggested to be associated with asthma 1302 and irritable bowel syndrome 1299.

Neuropeptide W/neuropeptide B receptors

Overview

The neuropeptide BW receptor 1 (NPBW1) is activated by two 23-amino-acid peptides, neuropeptide W (NPW-23 (NPW, Q8N729)) and neuropeptide B (NPB-23 (NPB, Q8NG41)) 1305,1309. C-terminally extended forms of the peptides (NPW-30 (NPW, Q8N729) and NPB-29 (NPB, Q8NG41)) also activate NPBW1 1304. Unique to both forms of NPB is the N-terminal bromination of the first tryptophan residue. des-Br-NPB-23 (NPB, Q8NG41) and des-Br-NPB-29 (NPB, Q8NG41) were not found to be major components of bovine hypothalamic tissue extracts. The NPBW2 receptor is activated by the short and C-terminal extended forms of NPB and NPW 1304.

Nomenclature	NPBW1 receptor	NPBW2 receptor
HGNC, UniProt	NPBWR1, P48145	NPBWR2, P48146
Principal transduction	Gi/0 1307	Gi/0 1307
Rank order of potency	NPB-29 > NPB-23 > NPW-23 > NPW-30 1304	NPW-23 > NPW-30 > NPB-29 > NPB-23 1304
Selective agonists (pKi)	Ava3 (9.37–9.43) 1306, Ava5 (8.8–9.0) 1306	–
Radioligands (Kd)	[125I]NPW-23 (human) (Agonist) (4.4x10−10 M) 1310	[125I]NPW-23 (human) (Agonist) (1.99x10−8 M) 1309

Comments

Potency measurements were conducted with heterologously-expressed receptors with a range of 0.14–0.57 nM (NPBW1) and 0.98–21 nM (NPBW2).

NPBW1^-/- mice show changes in social behavior, suggesting that the NPBW1 pathway may have an important role in the emotional responses of social interaction 1308.

Neuropeptide Y receptors

Overview

Neuropeptide Y (NPY) receptors (nomenclature agreed by NC-IUPHAR on Neuropeptide Y Receptors, 1325) are activated by the endogenous peptides NPY (NPY, P01303), NPY 3–36 (NPY, P01303), peptide YY (PYY (PYY, P10082)), PYY-(3–36) (PYY, P10082) and pancreatic polypeptide (PP (PPY, P01298)). The receptor originally identified as the Y3 receptor has been identified as the CXCR4 chemokine recepter (originally named LESTR, 1323). The y6 receptor is a functional gene product in mouse, absent in rat, but contains a frame-shift mutation in primates producing a truncated non-functional gene 1321. Many of the agonists exhibit differing degrees of selectivity dependent on the species examined. For example, the relative potency of PP (PPY, P01298) is greater at the rat Y₄ receptor than at the human receptor 1317. In addition, many agonists lack selectivity for individual subtypes, but can exhibit comparable potency against pairs of NPY receptor subtypes, or have not been examined for activity at all subtypes. [¹²⁵I]-PYY or [¹²⁵I]-NPY can be used to label Y₁, Y₂, Y₅ and Y₆ subtypes non-selectively, while [125I][cPP(1–7), NPY(19–23), Ala31, Aib32, Gln34]hPP may be used to label Y₅ receptors preferentially.

Nomenclature	Y1 receptor	Y2 receptor	Y4 receptor	Y5 receptor	y6 receptor
HGNC, UniProt	NPY1R, P25929	NPY2R, P49146	NPY4R, P50391	NPY5R, Q15761	NPY6R, Q99463
Principal transduction	Gi/o	Gi/o	Gi/o	Gi/o	Gi/o
Rank order of potency	NPY > PYY >> PP	NPY > PYY >> PP	PP > NPY = PYY	NPY > PYY > PP	NPY = PYY > PP
Endogenous agonists (pKi)	–	NPY 3–36 (Selective), PYY-(3–36) (9.2–9.7) 1318,1320	PP (8.7–10.9) 1311,1324,1327,1329	–	–
Selective agonists (pKi)	[Leu31,Pro34]PYY (human), [Pro34]NPY, [Pro34]PYY (human), [Leu31,Pro34]NPY (pEC50 7.1) 1314	–	–	[Ala31,Aib32]NPY (pig) (pIC50 8.2) 1313	–
Selective antagonists (pKi)	BIBP3226 (8.1–8.2) 1319,1326, BIBO3304 (pIC50 9.5) 1328	BIIE0246 (pIC50 8.5) 1315, JNJ-5207787 (pIC50 6.9–7.1) 1312	–	L-152,804 (7.6) 1322	–
Radioligands (Kd)	[125I][Leu31,Pro34]NPY (Agonist, Full agonist), [3H]BIBP3226 (Antagonist) (2.1x10−9 M)	[125I]PYY-(3–36) (human) (Agonist, Full agonist)	[125I]PP (human) (Agonist, Full agonist)	[125I][cPP(1–7), NPY(19–23), Ala31, Aib32, Gln34]hPP (Agonist) (5x10−10–7x10−10 M – Rat) 1316	–

Comments

The Y₁ agonists indicated are selective relative to Y₂ receptors. BIBP3226 is selective relative to Y₂, Y₄ and Y₅ receptors 1319. NPY-(13–36) is Y₂ selective relative to Y₁ and Y₅ receptors. PYY-(3–36) (PYY, P10082) is Y₂ selective relative to Y₁ receptors.

Neurotensin receptors

Overview

Neurotensin receptors (provisional nomenclature, 1330) are activated by the endogenous tridecapeptide neurotensin (pGlu-Leu-Tyr-Glu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu) derived from a precursor (NTS, P30990), which also generates neuromedin N, an agonist at the NTS₂ receptor. A nonpeptide antagonist, SR142948A, shows high affinity (pK_i∼9) at both NTS₁ and NTS₂ receptors 1331. [3H]neurotensin (human, mouse, rat) and [125I]neurotensin (human, mouse, rat) may be used to label NTS₁ and NTS₂ receptors at 0.1–0.3 and 3–5 nM concentrations respectively.

Nomenclature	NTS1 receptor	NTS2 receptor
HGNC, UniProt	NTSR1, P30989	NTSR2, O95665
Principal transduction	Gq/11	Gq/11
Rank order of potency	neurotensin > neuromedin N 1332	neurotensin = neuromedin N 1335
Selective agonists (pKi)	JMV449 1338	levocabastine (6.8) 1335,1337
Selective antagonists (pKi)	SR48692 (pIC50 7.5–8.2) 1331	–
Radioligands (Kd)	[3H]SR48692 (Antagonist) (3.2x10−9 M – Rat) 1333	–

Comments

neurotensin (NTS, P30990) appears to be a low-efficacy agonist at the NTS₂ receptor 1339, while the NTS₁ receptor antagonist SR48692 is an agonist at NTS2 receptors 1339. An additional protein, provisionally termed NTS3 (also known as NTR3, gp95 and sortilin; ENSG00000134243), has been suggested to bind lipoprotein lipase and mediate its degradation 1336. It has been reported to interact with the NTS₁ receptor 1334 and has been implicated in hormone trafficking and/or neurotensin uptake.

Opioid receptors

Overview

Opioid and opioid-like receptors are activated by a variety of endogenous peptides including [Met]enkephalin (PENK, P01210) (met), [Leu]enkephalin (PENK, P01210) (leu), β-endorphin (POMC, P01189) (β-end), α-neodynorphin (PDYN, P01213), dynorphin A (PDYN, P01213) (dynA), dynorphin B (PDYN, P01213) (dynB), big dynorphin (PDYN, P01213) (Big dyn), nociceptin/orphanin FQ (N/OFQ (PNOC, Q13519)); endomorphin-1 and endomorphin-2 are also potential endogenous peptides. The Greek letter names for the opioid receptors, μ, δ and κ, are well established, and IUPHAR considers these names most appropriate 1352. The human N/OFQ receptor is considered ‘opioid-related’ rather than opioid because while it exhibits a high degree of structural homology with the conventional opioid receptors 1368, it displays a distinct pharmacology.

Nomenclature	δ receptor	κ receptor	μ receptor	NOP receptor
HGNC, UniProt	OPRD1, P41143	OPRK1, P41145	OPRM1, P35372	OPRL1, P41146
Principal transduction	Gi/o	Gi/o	Gi/o	Gi/o
Rank order of potency	–	–	–	N/OFQ >> dynorphin A
Principal endogenous agonists	β-endorphin, [Leu]enkephalin, [Met]enkephalin	big dynorphin, dynorphin A	β-endorphin, [Met]enkephalin, [Leu]enkephalin, endomorphin-1, endomorphin-2	–
Endogenous agonists (pKi)	–	–	endomorphin-2 (Selective) (8.5 – Rat) 1388, endomorphin-1 (8.3) 1353,1388	N/OFQ (Selective) (9.7–10.4) 1341,1365–1367,1372
Selective agonists (pKi)	[D-Ala2]deltorphin I (pKd 9.35) 1350,1382, [D-Ala2]deltorphin II (8.8) 1351, DPDPE (8.8) 1369,1384, SNC80 (7.2) 1345,1376	enadoline (9.6) 1357,1370, U69593 (9.5) 1363,1384, U50488 (7.8–9.7) 1348,1373,1379,1384,1386,1392,1393, salvinorin A (7.8–8.7) 1343,1377	sufentanil (9.9) 1385, DAMGO (9.3) 1355,1384, PL017 (8.2) 1347,1384	N/OFQ-(1–13)-NH2 (10.1–10.4) 1341,1354,1365,1372, Ro64-6198 (9.6) 1358
Selective antagonists (pKi)	naltriben (10.0) 1381,1384, naltrindole (9.7) 1375,1384, TIPPψ (Inverse agonist) (9.0) 1378,1384	nor-binaltorphimine (8.9–11.0) 1373,1374,1379,1384,1392,1393, GNTI (9.74–9.9) 1359,1373,1383	CTAP (8.6) 1347,1384	UFP-101 (10.2) 1346, SB 612111 (9.5) 1391, J-113397 (pIC50 8.3) 1361
Radioligands (Kd)	[3H]deltorphin II 1344, [3H]DPDPE 1340, [3H]naltriben (Antagonist) 1364, [3H]naltrindole (Antagonist) 1387	[3H]CI977 1380, [3H]U69593 (Agonist, Full agonist) (2x10−9–1.6x10−9 M) 1363,1373,1379	[3H]DAMGO (Agonist, Full agonist) 1390, [3H]PL017 (Agonist) 1356	[3H]N/OFQ (Agonist, Full agonist) (6.3x10-11 M) 1349,1367

Comments

Subtypes of μ (μ1, μ2), δ (δ1, δ2) and κ (κ1, κ2, κ3) receptor have been proposed based primarily on binding studies with poorly selective ligands or results from in vivo studies. Only three naloxone-sensitive opioid receptors have been cloned, and while the μ-receptor in particular may be subject to extensive alternative splicing, these putative isoforms have not been definitively correlated with any of the proposed subtypes. Opioid receptor subtypes may reflect heterodimerization of opioid receptors with each other or with other GPCR 1360, but evidence for heterodimers in native cells is equivocal. A distinct met-enkephalin receptor lacking structural resemblance to the opioid receptors listed has been identified (OGFR, 9NZT2) and termed an opioid growth factor receptor 1389. Opioid receptor subtypes may reflect heterodimerization of opioid receptors with each other or with other GPCR, and while there is increasing evidence for heterodimers in native cells, the consequences this heterodimerization has for signalling remains largely unknown. For μ-opioid receptors at least, dimerization does not seem to be required for signalling 1362.

endomorphin-1 and endomorphin-2 have been identified as highly selective, putative endogenous agonists for the μ-opioid receptor. At present, however, the mechanisms for endomorphin synthesis in vivo have not been established, and there is no gene identified that encodes for either. Thus, the status of these peptides as endogenous ligands remains unproven.

Two areas of increasing importance in defining opioid receptor function are the presence of functionally relevant single nucleotide polymorphisms in human μ-receptors 1371 and the identification of biased signalling by opioid receptor ligands, in particular, compounds previously characterized as antagonists 1342. Pathway bias for agonists makes general rank orders of potency and efficacy somewhat obsolete, and they have, therefore, been removed from the table. As ever, the mechanisms underlying the acute and long term regulation of opiod receptor function are the subject of intense investigation and debate.

Orexin receptors

Overview

Orexin receptors (nomenclature as agreed by NC-IUPHAR, see 1395) are activated by the endogenous polypeptides orexin-A (HCRT, O43612) and orexin-B (HCRT, O43612) (also known as hypocretin-1 and -2; 33 and 28 aa) derived from a common precursor, preproorexin or orexin precursor, by proteolytic cleavage 1407. Binding to both receptors may be accomplished with [125I]orexin A (human, mouse, rat) 1397.

Nomenclature	OX1 receptor	OX2 receptor
HGNC, UniProt	HCRTR1, O43613	HCRTR2, O43614
Principal transduction	Gq/11	Gq/11
Rank order of potency	orexin-A > orexin-B	orexin-A = orexin-B
Selective agonists (pKi)	–	[Ala11, D-Leu15]orexin-B (pEC50 9.9) 1394
Selective antagonists (pKi)	SB-334867 (7.4 – 7.5) 1402,1404, SB-408124 (7.2 – 7.6) 1399,1402	N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulphonyl)-amino]-N-pyridin-3-ylmethyl-acetamide (9.0) 1401, 1-(2,4-dibromo-phenyl)-3-((4S,5S)-2,2-dimethyl-4-phenyl-[1394,1396]dioxan-5-yl)-urea (7.9 – 8.6) 1403, TCS-OX2-29 (7.4) 1396

Comments

The primary coupling of orexin receptors to G_q/11 proteins is rather speculative and based on the strong activation of phospholipase C. Coupling of both receptors to G_i/o and G_s has also been reported 1398,1406; for most cellular responses observed, the G protein pathway is unknown. The rank order of endogenous agonist potency may depend on the cellular signal transduction machinery. The synthetic [Ala11, D-Leu15]orexin-B may show poor OX₂ receptor selectivity 1405.

Loss-of-function mutations in the gene encoding the OX₂ receptor underlie canine hereditary narcolepsy 1400.

Oxoglutarate receptor

Overview

the oxoglutarate receptor (NC-IUPHAR recommended nomenclature, see Davenport et al., 2004) has been suggested to respond to one of the intermediates of the citric acid cycle 1408.

Nomenclature	HGNC gene symbol	UniProtKB AC	Principal transduction	Endogenous agonists (pKi)
oxoglutarate receptor	OXGR1	Q96P68	Gq 1408	α-ketoglutaric acid (pEC50 3.3 – 4.49) 1408,1409

P2Y receptors

Overview

P2Y receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on P2Y Receptors, 1410,1411) are activated by the endogenous ligands ATP, ADP, UTP, UDP and UDP-glucose. The relationship of many of the cloned receptors to endogenously expressed receptors is not yet established and so it might be appropriate to use wording such as ‘UTP-preferring (or ATP-, etc.) P2Y receptor’ or ‘P2Y₁-like’, etc., until further, as yet undefined, corroborative criteria can be applied.

Nomenclature	P2Y1 receptor	P2Y2 receptor	P2Y4 receptor	P2Y6 receptor
HGNC, UniProt	P2RY1, P47900	P2RY2, P41231	P2RY4, P51582	P2RY6, Q15077
Principal transduction	Gq/11	Gq/11	Gq/11	Gq/11
Rank order of potency	ADP>ATP	UTP=ATP	UTP>ATP (at rat recombinant receptors, UTP = ATP)	UDP>>UTP>ATP
Endogenous agonists (pKi)	–	–	–	UDP (pEC50 6.5) 1423
Selective agonists (pKi)	MRS2365 (pEC50 9.4) 1421, ADPβS (pEC50 7.3) 1459, 2MeSADP (pIC50 5.4 – 7.0) 1458,1461	2-thioUTP (pEC50 7.3) 1426, PSB1114 (pEC50 6.9) 1427, Ap4A (pEC50 6.1) 1419,1457, UTPγS (pEC50 5.8) 1443, MRS2768 (pEC50 5.7) 1441	UTPγS 1444, MRS4062 (pEC50 7.6) 1448	MRS2957 (pEC50 7.9) 1447, 5-iodoUDP (pEC50 7.82) 1416, 3-phenacyl-UDP (pEC50 7.2) 1426
Selective antagonists (pKi)	MRS2500 (8.8 – 9.1) 1420,1438, MRS2279 (7.9) 1461, MRS2179 (7.0 – 7.1) 1418,1461, 2,2'-pyridylisatogen tosylate (6.8) 1429	AR-C118925XX (pIC50 ∼6.0) 1436	ATP (pKd 6.2) 1437	MRS2578 (pIC50 7.4) 1445
Radioligands (Kd)	[35S]ADPβS (Agonist), [3H]2MeSADP (Agonist), [3H]MRS2279 (Antagonist) (8x10-9 M) 1461	–	–	–

Nomenclature	P2Y11 receptor	P2Y12 receptor	P2Y13 receptor	P2Y14 receptor
HGNC, UniProt	P2RY11, Q96G91	P2RY12, Q9H244	P2RY13, Q9BPV8	P2RY14, Q15391
Principal transduction	Gs, Gq/11	Gi/o	Gi/o	Gq/11
Rank order of potency	ATP>UTP	ADP>>ATP	ADP>>ATP	UDP-glucose
Endogenous agonists (pKi)	–	ADP (5.9) 1432, ATP (5.2) 1432	–	–
Selective agonists (pKi)	NAADP 1452, NAD 1453, AR-C67085 (pEC50 8.52) 1413,1424, NF546 (pEC50 6.27) 1449	2MeSADP (9.2) 1432	–	MRS2690 (pEC50 6.64 – 7.31) 1430,1442
Selective antagonists (pKi)	NF157 (7.35) 1460, NF340 (pIC50 6.4 – 7.1) 1449	PSB-0739 (7.6) 1414, ARL66096 (pIC50 7.95) 1433,1434	MRS2211 (pIC50 5.97) 1439	–
Radioligands (Kd)	–	[3H]PSB-0413 (Antagonist) (3.16x10-9 – 4.57x10-9 M) 1425,1455, [3H]2MeSADP (Agonist, Full agonist) (IC50 2.5x10-10 – 3.16x10-8 M) 1459	–	–

Comments

AR-C69931MX (cangrelor) shows selectivity for P2Y₁₂ and P2Y₁₃ receptors compared with other P2Y receptors 1446,1459. NF157 also has antagonist activity at P2X₁ receptors 1460. UDP has been reported to be an antagonist at the P2Y₁₄ receptor 1428.

An orphan GPCR suggested to be a ‘P2Y₁₅’ receptor 1435 appears not to be a genuine nucleotide receptor 1411, but rather responds to dicarboxylic acids 1431. Further P2Y-like receptors have been cloned from non-mammalian sources; a clone from chick brain, termed a p2y₃ receptor (ENSGALG00000017327), couples to the G_q/11 family of G proteins and shows the rank order of potency ADP > UTP > ATP = UDP 1462. In addition, human sources have yielded a clone with a preliminary identification of p2y5 (LPAR6, P43657) and contradictory evidence of responses to ATP 1440,1463. This protein is now classified as LPA4, a receptor for lysophosphatidic acid (LPA) 1456,1464. The clone clone termed p2y9 (LPAR4, 99677, 1454). The clone p2y7 (NOP9, Q86U38), originally suggested to be a P2Y receptor 1412, has been shown to encode a leukotriene receptor 1465. A P2Y receptor that was initially termed a p2y8 receptor (P79928) has been cloned from Xenopus laevis; it shows the rank order of potency ADPβS > ATP = UTP = GTP = CTP = TTP = ITP > ATPγS and elicits a Ca²⁺-dependent Cl- current in Xenopus oocytes 1417. The p2y10 clone (P2RY10, O00398) lacks functional data. Diadenosine polyphosphates also have effects on as yet uncloned P2Y-like receptors with the rank order of potency of Ap4A > Ap5a > Ap3a, coupling via G_q/11 1419. P2Y-like receptors have recently been described on mitochondria 1415. CysLT1 and CysLT2 leukotriene receptors respond to nanomolar concentrations of UDP, although they are activated principally by leukotrienes LTC4 and LTD4 1450,1451; Human GPR17 (13304) and rat GPR17, which are structurally related to CysLT and P2Y receptors, are also activated by leukotrienes as well as UDP and UDP-glucose 1422. Activity at the rat GPR17 is inhibited by submicromolar concentrations of MRS2179 and cangrelor 1422.

Parathyroid hormone receptors

Overview

The parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor (PTH₁ receptor) is activated by precursor-derived peptides: PTH (PTH, P01270) (84 amino acids), and PTHrP (PTHLH, P12272) (141 amino-acids) and related peptides (PTH-(1-34), PTHrP-(1-36)). The parathyroid hormone 2 receptor (PTH₂ receptor) is activated by the precursor-derived peptide TIP39 (39 amino acids, PTH2, Q96A98). [¹²⁵I]PTH may be used to label both PTH₁ and PTH₂ receptors.

Nomenclature	PTH1 receptor	PTH2 receptor
HGNC, UniProt	PTH1R, Q03431	PTH2R, P49190
Principal transduction	Gs, Gq/11	Gs, Gq/11
Rank order of potency	PTH = PTHrP	TIP39, PTH >> PTHrP
Endogenous agonists (pKi)	–	TIP39 (pIC50 7.6 – 9.2) 1468,1469
Selective agonists (pKi)	PTHrP-(1-34) (pIC50 7.8 – 8.1 - Rat) 1467, PTH-(1-34) (human) (pIC50 7.4) 1466	–

Comments

Although PTH (PTH, P01270) is an agonist at human PTH₂ receptors, it fails to activate the rodent orthologues. TIP39 (PTH2, Q96A98) is a weak antagonist at PTH₁ receptors 1470.

Peptide P518 receptor

Overview

The peptide P518 receptor is also known as the QRFP receptor and responds to the endogenous peptide agonist QRFP.

Nomenclature	HGNC, UniProt	Principal transduction	Endogenous agonists (pKi)	Radioligands (Kd)
QRFP receptor	QRFPR, Q96P65	Gq/11, Gi/o 1471	QRFP26 (QRFP) (pEC50 8.15) 1472, QRFP (QRFP, P83859) (pIC50 7.8 – 9.28 − Rat) 1471,1474	[125I]QRFP (human) (Agonist, Full agonist) (5.01x10-11 – 1.58x10-8 M) 1471,1473,1474

Comments

The orphan receptor GPR83 (9NYM4) shows sequence similarities with NPFF1, NPFF2, PrRP and QRFP receptors.

Platelet-activating factor receptor

Overview

Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is an ether phospholipid mediator associated with platelet coagulation, but also subserves inflammatory roles. The PAF receptor (provisional nomenclature, see 1475) is activated by PAF and other suggested endogenous ligands are oxidized phosphatidylcholine 1479 and lysophosphatidylcholine 1482. It may also be activated by bacterial lipopolysaccharide 1481.

Nomenclature	HGNC, UniProt	Principal transduction	Selective agonists (pKi)	Selective antagonists (pKi)	Radioligands (Kd)
PAF receptor	PTAFR, P25105	Gq/11, Gi, Go	mc-PAF	SR 27417 (10.3) 1478, L659989 (8.1), ginkgolide B (6.4), apafant (5.2 – 7.5) 1483,1484, CV-6209 (pIC50 8.1 – 8.3) 1477,1480	[3H]PAF (Agonist, Full agonist) (1.6x10-9 – 1.3x10-9 M) 1476,1480

Comments

Note that a previously recommended radioligand ([3H]apafant; K_d 44.6 nM) is currently unavailable.

Prokineticin receptors

Overview

Prokineticin receptors (provisional nomenclature, 1486) respond to the cysteine-rich 81–86 amino-acid peptides prokineticin-1 (PROK1, Q9HC23) (also known as endocrine-gland-derived vascular endothelial growth factor, mambakine) and prokineticin-2 (PROK2, Q9HC23) (protein Bv8 homologue). An orthologue of PROK1 from black mamba (Dendroaspis polylepis) venom, mamba intestinal toxin 1 (MIT1, 1491) is a potent, non-selective agonist at prokineticin receptors 1488, while Bv8, an orthologue of PROK2 from amphibians (Bombina sp., 1489), is equipotent at recombinant PK₁ and PK₂ receptors 1490, and has high potency in macrophage chemotaxis assays, which are lost in PK₁-null mice 1485.

Nomenclature	PKR1	PKR2
HGNC, UniProt	PROKR1, Q8TCW9	PROKR2, Q8NFJ6
Principal transduction	Gq/11 1487,1488	Gq/11 1487,1488
Rank order of potency	prokineticin-2 > prokineticin-1 1487,1488,1492	prokineticin-2 > prokineticin-1 1487,1488,1492

Prolactin-releasing peptide receptor

Overview

The precursor (PRLH, P81277) for PrRP generates 31 and 20-amino-acid versions. QRFP (QRFP, P83859) (named after a pyroglutamylated arginine-phenylalanine-amide peptide) is a 43 amino acid peptide derived from QRFP (P83859) and is also known as P518 or 26RFa. RFRP is an RF amide-related peptide 1495 derived from a FMRFamide-related peptide precursor (NPVF, Q9HCQ7), which is cleaved to generate neuropeptide NPSF (NPFF, O15130), neuropeptide RFRP-1 (NPVF, Q9HCQ7), neuropeptide RFRP-2 (NPVF, Q9HCQ7) and neuropeptide RFRP-3 (NPVF, Q9HCQ7) (neuropeptide NPVF).

Nomenclature	HGNC, UniProt	Principal transduction	Rank order of potency	Endogenous agonists (pKi)	Endogenous antagonists (pKi)	Radioligands (Kd)
PRRP receptor	PRLHR, P49683	Gq/11 1497	PrRP-20, PrRP-31 1497	PrRP-20 (Selective) (9.0–9.6) 1494,1497, PrRP-31 (Selective) (9.0–9.2) 1494,1497	NPY (NPY, P01303) (Selective) (5.4) 1496	[125I]PrRP31 1493, [125I]PrRP-20 (human) (Agonist, Full agonist) (2.6×10−11–5.7×10−10 M) 1497

Comments

The orphan receptor GPR83 (Q9NYM4) shows sequence similarities with NPFF1, NPFF2, PrRP and QRFP receptors.

Prostanoid receptors

Overview

Prostanoid receptors (nomenclature agreed by the NC-IUPHAR Subcommittee on Prostanoid Receptors, 1512) are activated by the endogenous ligands prostaglandins PGD2, PGE2, PGF2α, PGH2, prostacyclin [PGI2] and thromboxane A2. Measurement of the potency of PGI2 and thromboxane A2 is hampered by their instability in physiological salt solution; they are often replaced by cicaprost and U46619, respectively, in receptor characterization studies.

Nomenclature	DP1 receptor	DP2 receptor	FP receptor	IP1 receptor	TP receptor
HGNC, UniProt	PTGDR, Q13258	PTGDR2, Q9Y5Y4	PTGFR, P43088	PTGIR, P43119	TBXA2R, P21731
Principal transduction	Gs	Gi/o	Gq/11	–	Gq/11
Rank order of potency	PGD2 >> PGE2 > PGF2α > PGI2, thromboxane A2	PGD2 >> PGF2α, PGE2 > PGI2, thromboxane A2	PGF2α > PGD2 > PGE2 > PGI2, thromboxane A2	PGI2 >> PGD2, PGE2, PGF2α > thromboxane A2	thromboxane A2 = PGH2 >> GD2, PGE2, PGF2α, PGI2
Selective agonists (pKi)	L-644,698 (9.0–9.3) 1563,1564, BW 245C (8.4–9.4) 1506,1563,1564, SQ-27986 (8.0) 1545, RS 93520 (Partial agonist) (7.5) 1545, ZK118182 (7.3) 1545	15(R)-15-methyl-PGD2 (8.9) 1518,1533,1552, 13,14-dihydro-15-keto-PGD2 (7.4–8.5) 1518,1544,1552	fluprostenol (8.6) 1498, latanoprost (free acid form) (8.6) 1498, AL12180 (pEC50 7.7–7.9) 1547	cicaprost (7.8) 1498, AFP-07 (pIC50 8.5) 1508, BMY 45778 (pIC50 8.0) 1520	I-BOP (pKd 8.94–9.32) 1532, U46619 (7.5) 1498, STA2 (pIC50 6.38–7.06) 1502
Selective antagonists (pKi)	laropiprant (10.1) 1550, BWA868C (8.6–9.3) 1506,1517,1563, S-5751 (8.8) 1501	ramatroban (7.4) 1552, CAY 10471 (pIC50 8.92) 1543,1556	AS604872 (7.5) 1510	RO3244794 (pA2 8.5) 1503, RO1138452 (8.7) 1503	ifetroban (8.4–10.0) 1538, GR 32191 (8.3–9.4) 1502,1528, SQ-29548 (8.1–9.1) 1498,1554,1559, ONO 3708 (7.4–8.9) 1522
Radioligands (Kd)	[3H]PGD2 (Agonist, Full agonist) (1.3×10−8 – 3×10–10 M) 1559,1563	[3H]PGD2 (Agonist, Full agonist) (1.6×10–8 – 6×10–9 M) 1530,1548	[3H]PGF2α (Agonist, Full agonist) (7.9×10–9 – 1×10–9 M) 1498,1499,1559, [3H](+)-fluprostenol (Agonist) (3.4×10–8 M)	[3H]iloprost (Agonist, Full agonist) (2×10–8 – 1×10–9 M) 1498,1505,1559	[125I]BOP (Agonist, Full agonist) (2×10–9 M) 1534, [125I]SAP (Antagonist) (2×10–8 – 5×10–10 M) 1536, [3H]SQ-29548 (Antagonist) (4×10–8 – 6.3×10–9 M) 1498,1559

Nomenclature	EP1 receptor	EP2 receptor	EP3 receptor	EP4 receptor
HGNC, UniProt	PTGER1, P34995	PTGER2, P43116	PTGER3, P43115	PTGER4, P35408
Principal transduction	Gq/11	Gs	Gi/o	Gs
Rank order of potency	PGE2 > PGF2α, PGI2 > PGD2, thromboxane A2	PGE2 > PGF2α, PGI2 > PGD2, thromboxane A2	PGE2 > PGF2α, PGI2 > PGD2, thromboxane A2	PGE2 > PGF2α, PGI2 > PGD2, thromboxane A2
Selective agonists (pKi)	17-phenyl-ω-trinor-PGE2 (8.1) 1546, ONO-DI-004 (6.8 - Mouse) 1553	ONO-AE1-259 (8.5 - Mouse) 1553, butaprost (free acid form) (5.9–7.0) 1498,1549, CP-533536 (pIC50 7.3 - Rat) 1507	SC46275 (pEC50 8.74 - Rat) 1519, ONO-AE-248 (pEC50 5.64–6.7) 1514,1527	L902688 (pEC50 8.05–10.3) 1515,1525, ONO-AE1-329 (pEC50 7.66–7.8) 1514,1515, CP734432 (pIC50 8.7) 1540
Selective antagonists (pKi)	ONO-8711 (9.2) 1557, SC-51322 (7.9) 1498, GW848687X (pIC50 8.6) 1516	–	L-798,106 (9.52–9.62) 1521,1551, ONO-AE3-240 (pIC50 8.8 - Mouse) 1500	MK-2894 (9.25) 1498,1504,1511, CP-533536 (8.6) 1535, ONO-AE3-208 (8.5), EP4A (7.6–8.5) 1529,1565, BGC201531 (7.9) 1531, GW 627368 (7.0–7.1) 1559,1560, ER819762 (pIC50 7.15) 1509
Radioligands (Kd)	[3H]PGE2 (Agonist, Full agonist) (1×10–9 – 2.5×10–8 M) 1498,1546,1559	[3H]PGE2 (Agonist, Full agonist) (1.25×10–8 – 1.99×10–8 M) 1498,1559	[3H]PGE2 (Agonist, Full agonist) (3×10–10 – 7×10–9 M) 1498,1559	[3H]PGE2 (Agonist, Full agonist) (2.4×10–8 – 3×10–10 M) 1498,1513,1558,1559

Comments

ramatroban is also a TP receptor antagonist. cicaprost exhibits moderate EP₄ receptor agonist potency 1498. iloprost also binds to EP₁ receptors. The TP receptor exists in α and β isoforms due to alternative splicing of the cytoplasmic tail 1542.

17-phenyl-ω-trinor-PGE2 also shows agonist activity at EP₃ receptors. sulprostone also has affinity for EP₁ receptors. butaprost and SC46275 may require de-esterification within tissues to attain full agonist potency. There is evidence for subtypes of FP 1526, IP 1555,1561 and TP 1524 receptors. mRNA for the EP₁ and EP₃ receptors undergo alternative splicing to produce two 1539 and at least six variants, respectively, which can interfere with signalling 1539 or generate complex patterns of G-protein (G_i/o, G_q/11, G_s and G_12,13) coupling (e.g. 1523,1537). The possibility of additional receptors for the isoprostanes has been suggested 1541. Receptors (prostamide F, which as yet lack a molecular correlate) that preferentially recognize PGF2-1-ethanolamide and its analogues (e.g. bimatoprost) have been identified, together with moderate-potency antagonists (e.g. AGN 211334) 1562.

The free acid form of AL-12182, AL-12180, used in in vitro studies, has a EC₅₀ value of 15nM which is the concentration of the compound giving half-maximal stimulation of IP turnover in HEK-293 cells expressing the human FP receptor 1547.

References given alongside the TP receptor agonists I-BOP 1532 and STA₂ 1502 use human platelets as the source of TP receptors for competition radio-ligand binding assays to determine the indicated activity values.

Proteinase-activated receptors

Overview

Proteinase-activated receptors (PARs, nomenclature as agreed by NC-IUPHAR Subcommittee on Protease-activated Receptors, 1574) are unique members of the GPCR superfamily activated by proteolytic cleavage of their amino terminal exodomains. Agonist proteinase-induced hydrolysis unmasks a tethered ligand (TL) at the exposed amino terminus, which acts intramolecularly at the binding site in the body of the receptor to effect transmembrane signalling. TL sequences at human PAR1–4 are SFLLRN-NH2, SLIGKV-NH2, TFRGAP-NH2 and GYPGQV-NH2, respectively. With the exception of PAR3, these synthetic peptide sequences (as carboxyl terminal amides) are able to act as agonists at their respective receptors. Several proteinases, including neutrophil elastase, cathepsin G and chymotrypsin can have inhibitory effects at PAR1 and PAR2 such that they cleave the exodomain of the receptor without inducing activation of Gαq-coupled calcium signaling, thereby preventing activation by activating proteinases but not by agonist peptides. Neutrophil elastase cleavage of PAR2 can however activate MAP kinase signaling by exposing a TL that is different from the one revealed by trypsin 1581. The role of such an action in vivo is unclear.

Nomenclature	PAR1	PAR2	PAR3	PAR4
HGNC, UniProt	F2R, P25116	F2RL1, P55085	F2RL2, O00254	F2RL3, Q96RI0
Principal transduction	Gq/11/Gi/o/G12/13	Gq/11/Gi/o	Not known	Gq/11/Gi/o
Agonist proteases	thrombin (F2, P00734), activated protein C (PROC, P04070), matrix metalloproteinase 1 (MMP1, P45452), matrix metalloproteinase 13 (MMP13, P45452) 1569	Trypsin, tryptase, TF/VIIa, Xa	thrombin (F2, P00734)	thrombin (F2, P00734), trypsin, cathepsin G (CTSG, P08311)
Selective agonists (pKi)	TFLLR-NH2 (pEC50 5.41) 1573	SLIGKV-NH2 1579, SLIGRL-NH2 1579, 2-furoyl-LIGRLO-amide (5.4) 1580, GB 110 (pEC50 6.55) 1570,	–	AYPGKF-NH2, GYPGKF-NH2, GYPGQV-NH2
Selective antagonists (pKi)	SCH530348 (8.09) 1572, atopaxar (pIC50 7.72) 1578, RWJ-56110 (pIC50 6.36) 1568	P2pal18s 1582, GB88 (pIC50 5.7) 1583	–	–
Radioligands (Kd)	[3H]haTRAP (Agonist) (1.5x10-8 M) 1566	2-furoyl-LIGRL[N[3H]propionyl]-O-NH2 1575, [3H]2-furoyl-LIGRL-NH2 (Agonist) 1576, trans-cinnamoyl-LIGRLO [N-[3H]propionyl]-NH2 1567	–	–

Comments

TFLLR-NH2 is selective relative to the PAR₂ receptor 1571,1577. thrombin (F2, P00734) is inactive at the PAR₂ receptor.

Endogenous serine proteases (EC 3.4.21.) active at the proteinase-activated receptors include: thrombin (F2, P00734), generated by the action of Factor X (F10, P00742) on liver-derived prothrombin (F2, P00734); trypsin, generated by the action of enterokinase (TMPRSS15, P98073) on pancreatic-derived trypsinogen (PRSS1, P07477); tryptase, a family of enzymes (α/β1 TPSAB1, Q15661; γ1 TPSG1, Q9NRR2; δ1 TPSD1, Q9BZJ3) secreted from mast cells; cathepsin G (CTSG, P08311) generated from leukocytes; liver- derived protein C (PROC, P04070) generated in plasma by thrombin (F2, P00734) and matrix metalloproteinase 1 (MMP1, P45452).

2-Furoyl-LIGRLO-NH₂ activity was measured via calcium mobilisation in HEK 293 cells which constitutively coexpress human PAR₁ and PAR₂.

Relaxin family peptide receptors

Overview

Relaxin family peptide receptors (RXFP, nomenclature as recommended by the NC-IUPHAR committee on relaxin family peptide receptors, 1584) may be divided into two pairs, RXFP1/2 and RXFP3/4. Endogenous agonists at these receptors are a number of heterodimeric peptide hormones analogous to insulin: H1 relaxin (RLN1, P04808), H2 relaxin (RLN2, P04090), H3 relaxin (RLN3, Q8WXF3) (also known as INSL7), insulin-like peptide 3 (INSL3 (INSL3, P51460)) and INSL5 (INSL5, Q9Y5Q6).

Species homologues of relaxin have distinct pharmacology – H2 relaxin (RLN2, P04090) interacts with RXFP1, RXFP2 and RXFP3, whereas mouse and rat relaxin selectively bind to and activate RXFP1 1611 and porcine relaxin may have a higher efficacy than H2 relaxin (RLN2, P04090) 1591. H3 relaxin (RLN3, Q8WXF3) has differential affinity for RXFP2 receptors between species; mouse and rat RXFP2 have a higher affinity for H3 relaxin (RLN3, Q8WXF3) 1610. At least two binding sites have been identified on the RXFP1 and RXFP2 receptors: a high-affinity site in the leucine-rich repeat region of the ectodomain and a somewhat lower-affinity site located in the surface loops of the transmembrane domain 1591,1618. The unique N-terminal LDLa module of RXFP1 and RXFP2 is essential for receptor signalling 1612.

Nomenclature	RXFP1 receptor	RXFP2 receptor	RXFP3 receptor	RXFP4 receptor
HGNC, UniProt	RXFP1, Q9HBX9	RXFP2, Q8WXD0	RXFP3, Q9NSD7	RXFP4, Q8TDU9
Principal transduction	Gs, GαoB, Gαι3 1590,1595,1599	Gs, GαoB 1590,1601	Gi/o 1606,1620	Gi/o 1604
Rank order of potency	H2 relaxin > H3 relaxin >> INSL3 1618	INSL3 > H2 relaxin >> H3 relaxin 1601,1618	H3 relaxin > H3 relaxin (B chain) 1604	INSL5 = H3 relaxin > H3 relaxin (B chain) 1602,1603
Endogenous antagonists (pKi)	–	–	INSL5 (pIC50 6.3) 1605	–
Selective antagonists (pKi)	LGR7-truncate 1612, B-R13/17K H2 relaxin (pEC50 6.7) 1597,	(des 1-8) A-chain INSL3 analogue 1586, INSL3 B-chain analogue 1587, INSL3 B chain dimer 1616,	H3 relaxin analogue 3 1613, R3(BΔ23-27)R/I5 chimeric peptide (pIC50 9.2) 1600, R3-B1-22R (pIC50 7.4) 1596	R3(BΔ23-27)R/I5 chimeric peptide (pIC50 8.64) 1600
Radioligands (Kd)	[125I]H2 relaxin (Agonist, Full agonist), [33P]H2 relaxin (Agonist, Full agonist) (5x10-10–2x10-10 M) 1591,1618,	[125I]INSL3 (human) (Agonist, Full agonist) (1x10-10 M) 1608, [33P]H2 relaxin (Agonist, Full agonist) (1.06x10-9–6.3x10-10 M) 1591,1618,	[125I]H3 relaxin (Agonist, Full agonist) (3x10-10 M) 1604, [125I]H3-B/INSL5 A chimera (Agonist) (5x10-10 M) 1602,	[125I]H3 relaxin (Agonist, Full agonist) (2x10-9–2x10-10 M) 1603, [125I]H3-B/INSL5 A chimera (Agonist) (1.2x10-9 M) 1602,
Comment	europium-labelled H2 relaxin is a fluorescent ligand for this receptor (Kd=0.5 nM) 1614.	europium-labelled INSL3 is a fluorescent ligand for this receptor (Kd=1 nM) 1615.	europium-labelled H3-B/INSL5 A chimera is a fluorescent ligand for this receptor (Kd=5 nM) 1596.	europium-labelled H3-B/INSL5 A chimera is a fluorescent probe at this receptor (Kd=5 nM) 1596, europium-labelled mouse INSL5 is a fluorescent ligand at this receptor (Kd=5 nM) 1585.

Comments

H2 relaxin has recently successfully completed a Phase III clinical trial for the treatment of acute heart failure. 48 hr infusion of H2 relaxin reduced dyspnoea and 180 day mortality 1607. Small molecule agonists active at RXFP1 receptors have been developed 1617,1622. Mutations in INSL3 and LGR8 (RXFP2) have been reported in populations of patients with cryptorchidism 1588. Numerous splice variants of the human RXFP1 and RXFP2 receptors have been identified, most of which do not bind relaxin family peptides 1608. Splice variants of RXFP1 encoding the N-terminal LDLa module act as antagonists of RXFP1 signalling 1610,1612. cAMP elevation appears to be a major signalling pathway for RXFP1 and RXFP2 1598,1599, but RXFP1 also activates MAP kinases, nitric oxide signalling and interacts with tyrosine kinases and glucocorticoid receptors 1594. RXFP1 signalling involves lipid rafts, residues in the C-terminus of the receptor and activation of phosphatidylinositol-3-kinase 1595. More recent studies provide evidence that RXFP1 is pre-assembled in signalosomes with other signalling proteins including Gα_s, Gβγ and adenyl cyclase 2 that display constitutive activity and are exquisitely sensitive to sub-picomolar concentrations of relaxin 1592. The cAMP signalling pattern is highly dependent on the cell type in which RXFP1 is expressed 1593.

The receptor expression profiles suggest that RXFP3 is a neuropeptide receptor and RXFP4 a gut hormone receptor. The relaxin 3 RXFP3 system has roles in feeding and anxiety 1589,1609. H3 relaxin (RLN3, Q8WXF3) acts as an agonist at both RXFP3 and RXFP4 whereas INSL5 (INSL5, Q9Y5Q6) is an agonist at RXFP4 and a weak antagonist at RXFP3. Unlike RXFP1 and RXFP2 both RXFP3 and RXFP4 are encoded by a single exon and therefore no splice variants exist. The rat RXFP3 sequence has two potential start codons that encode RXFP3L and RXFP3S with the longer variant having an additional 7 amino-acids at the N-terminus. It is not known which variant is expressed. Rat and dog RXFP4 sequences are pseudogenes 1621. RXFP3 couples to G_i/o and inhibits adenylyl cyclase 1604,1619, and also causes Erk1/2 phosphorylation 1619. Relatively little is known about RXFP4 signalling but like RXFP3 it couples to inhibitory G-proteins 1605. Recent studies suggest that H2 relaxin (RLN2, P04090) also interacts with RXFP3 to cause a pattern of activation of signalling pathways that are a subset of those activated by H3 relaxin (RLN3, Q8WXF3). The two patterns of signaling observed in several cell types expressing RXFP3 are strong inhibition of forskolin-stimulated cAMP accumulation, ERK1/2 activation and nuclear factor NFκ-B reporter gene activation with H3 relaxin (RLN3, Q8WXF3), and weaker activity with H2 relaxin (RLN2, P04090), porcine relaxin, or insulin-like peptide 3 (INSL3 (INSL3, P51460)) and a strong stimulation of activator protein (AP)-1 reporter genes with H2 relaxin (RLN2, P04090), and weaker activation with H3 relaxin (RLN3, Q8WXF3) or porcine relaxin 1619. Two pharmacologically distinct ligand binding sites were also identified on RXFP3-expressing cells using [125I]H3-B/INSL5 A chimera which binds with high affinity with competition by H3 relaxin (RLN3, Q8WXF3) or a H3 relaxin (B chain) (RLN3, Q8WXF3) peptide, and [125I]H2 relaxin which displays competition by H2 relaxin (RLN2, P04090), H3 relaxin (RLN3, Q8WXF3), or INSL3 (INSL3, P51460) and weakly by porcine relaxin. Thus at RXFP3, H2 relaxin (RLN2, P04090) is a biased ligand compared to the cognate ligand H3 relaxin (RLN3, Q8WXF3).

Somatostatin receptors

Overview

Somatostatin (somatotropin release inhibiting factor) is an abundant neuropeptide, which acts on five subtypes of somatostatin receptor (sst₁–sst₅; nomenclature approved by the NC-IUPHAR Subcommittee on Somatostatin Receptors, 1628). Activation of these receptors produces a wide range of physiological effects throughout the body including inhibiting the secretion of many hormones. The relationship of the cloned receptors to endogenously expressed receptors is not yet well established in some cases. Endogenous ligands for these receptors are somatostatin-14 (SRIF-14 (SST, P61278)) and somatostatin-28 (SRIF-28 (SST, P61278)). Cortistatin (CST-14) has also been suggested to be an endogenous ligand for somatostatin receptors 1625.

Nomenclature	sst1 receptor	sst2 receptor	sst3 receptor	sst4 receptor	sst5 receptor
HGNC, UniProt	SSTR1, P30872	SSTR2, P30874	SSTR3, P32745	SSTR4, P31391	SSTR5, P35346
Principal transduction	Gi	Gi	Gi	Gi	Gi
Selective agonists (pKi)	L-797,591 (8.8) 1635, Des-Ala1,2,5-[D-Trp8,IAmp9]SRIF (pIC50 7.5) 1626	L-054,522 (11.0) 1640, MK-678 (8.8 – 10.3) 1623,1634,1636–1638,1640, octreotide (8.7 – 9.9) 1623,1634,1636–1638,1640, BIM 23027 (pIC50 10.85) 1624	L-796,778 (7.6) 1635	L-803,087 (9.2) 1635, NNC269100 (8.2) 1631	L-817,818 (9.4) 1635, BIM 23268 (8.7) 1632, BIM 23052 (7.4 – 9.6) 1632,1636–1638
Selective antagonists (pKi)	SRA880 (pKd 8.0 – 8.1) 1629	[D-Tyr8]CYN 154806 (pKd 8.1 – 8.9) 1633	NVP ACQ090 (7.9) 1630	–	BIM 23627 (pIC50 7.1) 1639
Radioligands (Kd)	–	[125I]Tyr3 SMS 201-995 (Agonist, Full agonist) (1.3x10-10 M) 1637,1638, [125I]BIM23027 (Agonist, Full agonist) (IC50 2.2x10-10 M - Rat) 1627	–	–	[125I]Tyr3 SMS 201-995 (Agonist, Full agonist) (2.3x10-10 M) 1637,1638

Comments

[125I]Tyr11-SRIF-14, [125I]LTT-SRIF-28, [125I]CGP 23996 and [125I]Tyr10-CST14 may be used to label somatostatin receptors nonselectively; BIM 23052 is said to be selective in rat but not human receptor 1634. A number of nonpeptide subtype-selective agonists have been synthesised 1635.

Succinate receptor

Overview

the succinate receptor (NC-IUPHAR recommended nomenclature, see Davenport et al., 2004) has been reported to respond to an intermediate of the citric acid cycle 1641.

Nomenclature	HGNC, UniProt	Principal transduction	Endogenous agonists (pKi)
succinate receptor	SUCNR1, Q9BXA5	–	succinic acid (pEC50 3.1–4.7) 1641,1642

Tachykinin receptors

Overview

Tachykinin receptors (provisional nomenclature, 1658) are activated by the endogenous peptides substance P (TAC1, P20366) (SP), neurokinin A (TAC1, P20366) (NKA; previously known as substance K, neurokinin α, neuromedin L), neurokinin B (TAC3, Q9UHF0) (NKB; previously known as neurokinin β, neuromedin K), neuropeptide K (TAC1, P20366) and neuropeptide γ (TAC1, P20366) (N-terminally extended forms of neurokinin A). The neurokinins (A and B) are mammalian members of the tachykinin family, which includes peptides of mammalian and nonmammalian origin containing the consensus sequence: Phe-x-Gly-Leu-Met. Marked species differences in in vitro pharmacology exist for all three receptors, in the context of nonpeptide ligands.

Nomenclature	NK1 receptor	NK2 receptor	NK3 receptor
HGNC, UniProt	TACR1, P25103	TACR2, P21452	TACR3, P29371
Principal transduction	Gq/11	Gq/11	Gq/11
Rank order of potency	substance P > neurokinin A > neurokinin B	neurokinin A > neurokinin B >> substance P	neurokinin B > neurokinin A > substance P
Selective agonists (pKi)	[Pro9]SP, septide (7.0–9.3) 1645,1663, [Sar9,Met(O2)11]SP (pIC50 9.7–9.9) 1673, substance P-OMe (pIC50 7.4–7.5) 1673	[βAla8]neurokinin A-(4–10) (pKd 6.0) 1656, GR64349 (pEC50 8.4 – Rat) 1653, [Lys5,Me-Leu9,Nle10]NKA-(4–10) (pIC50 8.8–9.4 – Rat) 1667	[Phe(Me)7]neurokinin B (8.7–9.6) 1670,1671, senktide (7.1–8.6) 1670,1671,1673
Selective antagonists (pKi)	aprepitant (10.7) 1662, LY303870 (9.8–10.0) 1660, CP 99994 (9.3–9.7) 1643,1671, LY303870 (pIC50 9.82) 1664, SR 140,333 (pIC50 8.9–9.0) 1673, RP67580 (pIC50 7.7) 1657	GR159897 (pKd 7.8–9.5) 1647,1656,1672, GR94800 (9.8) 1649, saredutant (9.4–9.7) 1643,1656,1671, MEN10627 (9.2), nepadutant (8.5–8.7) 1650,1652	osanetant (8.4–9.7) 1643,1644,1651,1655,1665,1668,1670,1671,1673, SB 223412 (7.4–9.0) 1646,1659,1670,1671, PD157672 (pIC50 7.8) 1648
Radioligands (Kd)	[125I]SP (human, mouse, rat) (Agonist, Full agonist), [18F]SPA-RQ (Antagonist), [3H]BH-[Sar9,Met(O2)11]SP, [3H]SP (human, mouse, rat) (Agonist, Full agonist), [125I]L703,606 (Antagonist) (3x10−10 M), [125I]BH-[Sar9,Met(O2)11]SP (Agonist, Full agonist) (1x10−9 M – Rat) 1674	[125I]NKA (human, mouse, rat), [3H]GR100679, [3H]SR48,968 (Antagonist) (2x10−10 M – Rat) 1661	[125I][MePhe7]NKB, [3H]senktide, [3H]SR142,801 (Antagonist) (1.3x10−10 M)

Comments

The NK₁ receptor has also been described to couple to other G proteins 1669. The hexapeptide agonist septide appears to bind to an overlapping but non-identical site to substance P (TAC1, P20366) on the NK₁ receptor. There are suggestions for additional subtypes of tachykinin receptor; an orphan receptor (SwissProt P30098) with structural similarities to the NK₃ receptor was found to respond to NKB when expressed in Xenopus oocytes or Chinese hamster ovary cells 1654,1666.

Thyrotropin-releasing hormone receptors

Overview

Thyrotropin-releasing hormone (TRH) receptors (provisional nomenclature) are activated by the endogenous tripeptide TRH (TRH, P20396) (pGlu-His-ProNH2). TRH (TRH, P20396) and TRH analogues fail to distinguish TRH₁ and TRH₂ receptors 1677. [3H]TRH (human, mouse, rat) is able to label both TRH₁ and TRH₂ receptors with K_d values of 13 and 9 nM respectively.

Nomenclature	TRH1 receptor	TRH2 receptor
HGNC, UniProt	TRHR, P34981	Trhr2, Q9ERT2
Principal transduction	Gq	Gq
Selective antagonists (pKi)	midazolam (5.49 - Rat) 1675, diazepam (5.15 - Rat) 1675, chlordiazepoxide (4.82 - Rat) 1675, chlordiazepoxide (4.7 - Mouse) 1676	–
Comment	–	A class A G protein-coupled receptor: not present in man

Comments

The human orthologue of the rodent TRH₂ receptor has yet to be identified.

Trace amine receptor

Overview

Trace amine-associated receptors (nomenclature as agreed by NC-IUPHAR for trace amine receptors, 1680) were initially discovered as a result of a search for novel 5-HT receptors 1678, where 15 mammalian orthologues were identified and divided into two families. The TA₁ receptor has been shown to have affinity for the endogenous trace amines tyramine, β-phenylethylamine and octopamine in addition to the classical amine dopamine 1678. Emerging evidence suggests that TA₁ is a modulator of monoaminergic activity in the brain 1683 with TA₁ and dopamine D₂ receptors shown to form constitutive heterodimers when co-expressed 1679.

Nomenclature	HGNC, UniProt	Principal transduction	Rank order of potency	Radioligands (Kd)
TA1 receptor	TAAR1 (Hs), Taar1 (Mm), Taar1 (Rn), Q96RJ0	Gs	tyramine > β-phenylethylamine > octopamine = dopamine 1678	[3H]tyramine (Agonist, Full agonist) (2x10−8 M) 1678

Comments

The product of the gene TAAR2 (also known as GPR58) appears to respond to β-phenylethylamine > tyramine and to couple through G_s 1678 See Orphan GPCR (Page 1462).

TAAR3, in some individuals, and TAAR4 are pseudogenes in man, although functional in rodents. The signalling characteristics and pharmacology of TAA5 (PNR, Putative Neurotransmitter Receptor: TAAR5, O14804), TAA6 (Trace amine receptor 4, TaR-4: TAAR6, 96RI8), TAA8 (Trace amine receptor 5, GPR102: TAAR8, Q969N4) and TAA9 (trace amine associated receptor 9: TAAR9, 96RI9) are lacking. The thyronamines, endogenous derivatives of thyroid hormone, have been shown to have affinity for rodent cloned trace amine receptors, including TA₁ 1681. An antagonist EPPTB has recently been described that has a pK_i of 9.1 at the mouse TA₁ but less than 5.3 for human TA₁ 1682.

Urotensin receptor

Overview

The urotensin-II (U-II) receptor (UT, nomenclature as agreed by NC-IUPHAR, 1691,1694) is activated by the endogenous dodecapeptide U-II (UTS2, O95399), originally isolated from the urophysis, the endocrine organ of the caudal neurosecretory system of teleost fish 1685. Several structural forms of U-II exist in fish and amphibians. The Goby orthologue was used to identify U-II as the cognate ligand for the predicted receptor encoded by the rat gene gpr14 1689,1700,1702,1703. Human U-II (UTS2, O95399), an 11-amino-acid peptide 1689, retains the cyclohexapeptide sequence of goby U-II that is thought to be important in ligand binding 1686,1696. This sequence is also conserved in the deduced amino-acid sequence of rat U-II (14 amino-acids) and mouse U-II (14 amino-acids), although the N-terminal is more divergent from the human sequence 1688. A second endogenous ligand for UT has been discovered in rat 1707. The urotensin II-related peptide (URP (UTS2B, Q765I0)), an octapeptide, is derived from a different gene, but shares the C-terminal sequence (CFWKYCV) common to U-II from other species. Identical sequences to rat URP (UTS2B, Q765I0) are predicted for the mature mouse and human peptides.

Nomenclature	HGNC, UniProt	Principal transduction	Endogenous agonists (pKi)	Selective agonists (pKi)	Selective antagonists (pKi)	Radioligands (Kd)
UT receptor	UTS2R, Q9UKP6	Gq/11	U-II (8.6) 1692,1693,1695	[Pen5]-U (4–11) (human) (9.7) 1695, U-II-(4–11) (human) (9.6) 1695, AC-7954 (6.6) 1690,1698, FL104 (pEC50 5.8 – 7.5) 1697,1699	urantide (8.3) 1704, SB-706375 (8.0) 1692, SB-611812 (6.6) 1705, palosuran (pIC50 7.1) 1687	[125I]U-II (human) (Agonist, Full agonist) (4x10-10 – 2.4x10-10 M) 1684,1701

Comments

In human vasculature, human U-II (UTS2, O95399) elicits both vasoconstrictor (pD₂ 9.3–10.1, 1701) and vasodilator (pIC₅₀ 10.3–10.4, 1706) responses.

Vasopressin and oxytocin receptors

Overview

Vasopressin (AVP) and oxytocin (OT) receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on vasopressin and oxytoxcin receptors) are activated by the endogenous cyclic nonapeptides AVP (AVP, P01178) and oxytocin (OXT, P01178) (OT). These peptides are derived from precursors which also produce neurophysins (neurophysin I for OT; neurophysin II for AVP).

Nomenclature	V1A receptor	V1B receptor	V2 receptor	OT receptor
HGNC, UniProt	AVPR1A, P37288	AVPR1B, P47901	AVPR2, P30518	OXTR, P30559
Principal transduction	Gq/11	Gq/11	Gs	Gq/11, Gi/o
Rank order of potency	AVP > oxytocin	AVP > oxytocin	AVP > oxytocin	oxytocin > AVP
Selective agonists (pKi)	F180 (pKd 7.9 – 8.3) 1711,1719	d[Leu4]LVP (9.8) 1731, d[Cha4]AVP (9.0 – 9.7) 1721,1726, d[D-Pal2]AVP (7.9) 1715,1721	d[Val4,DArg8]VP, OPC-51803 (7.0) 1730, VNA932 (pIC50 7.1) 1723	[Thr4,Gly7]OT (8.2 – 8.4) 1718,1722,1727
Selective antagonists (pKi)	d(CH2)5[Tyr(Me)2,Arg8]VP (9.0), SR 49059 (8.1 – 9.3) 1708,1719,1726,1732,1735,1738,1740–1742, conivaptan (8.2 – 8.4) 1738,1739	SSR149415 (8.4 – 9.3) 1725,1726,1737	tolvaptan (9.37) 1743, lixivaptan (Inverse agonist) (8.9 – 9.2) 1710,1735, SR 121463A (8.4 – 9.3) 1708,1719,1720,1734,1735,1738,1742, d(CH2)5[D-Ile2,Ile4]AVP (6.9 – 8.4) 1735, OPC-31260 (Inverse antagonist) (7.6) 1744	SSR126768A (8.82 – 9.05) 1736, L-371,257 (8.8) 1726, desGlyNH2-d(CH2)5[Tyr(Me)2,Thr4,Orn8]OT (8.5), L-372662 (8.4) 1712
Radioligands (Kd)	[3H]SR49059 (Antagonist), [125I]OH-LVA (Antagonist) (3.99x10-11 – 5x10-11 M) 1717,1719,1732, [3H]AVP (Agonist, Full agonist) (2.51x10-9 – 6.3x10-11 M) 1714,1717,1719,1720,1730,1732,1733,1738–1743, [3H]d(CH2)5[Tyr(Me)2]AVP (Antagonist) (1.1x10-9 M)	[3H]SSR149415 (Antagonist), [3H]AVP (Agonist, Full agonist) (2.51x10-9 – 2.5x10-10 M) 1714,1717,1719,1720,1730,1732,1733,1738–1743	[3H]AVP (Agonist, Full agonist) (3.98x10-9 – 3.99x10-10 M) 1717,1719,1720,1730,1733,1738,1739,1741–1743, [3H]SR 121463A (Antagonist, Inverse agonist) (4.1x10-9 – 5x10-10 M) 1720,1734, [3H]desGly-NH2[D-Ile2,Ile4]VP (2.8x10-9 M), [3H]dDAVP (Agonist, Full agonist) (6.3x10-8 – 8x10-10 M) 1717,1720,1741	[35S]non-peptide OT antagonist (Antagonist) (4.2x10-11 M) 1729, [125I]d(CH2)5[Tyr(Me)2,Thr4,Orn8,Tyr-NH29]OVT (Antagonist) (9x10-11 M), [3H]OT (human, mouse, rat) (Agonist, Full agonist) 1717,1724,1727,1728, [111In]DOTA-dLVT (4.5x10-9 M) 1716

Comments

The V₂ receptor exhibits marked species differences, such that many ligands (d(CH2)5[D-Ile2,Ile4]AVP and [3H]desGly-NH2[D-Ile2,Ile4]VP) exhibit low affinity at human V₂ receptors 1709. Similarly, [3H]d[D-Arg8]VP is V₂ selective in the rat, not in the human 1733. The gene encoding the V₂ receptor is polymorphic in man, underlying nephrogenic diabetes insipidus 1713. d[Cha4]AVP is selective only for the human and bovine V_1b receptors 1721, while d[Leu4]LVP has high affinity for the rat V_1b receptor 1731.

VIP and PACAP receptors

Overview

Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) receptors (nomenclature recommended by the NC-IUPHAR Subcommittee on Vasoactive Intestinal Peptide Receptors, 1749) are activated by the endogenous peptides VIP (VIP, P01282), PACAP-38 (ADCYAP1, P18509), PACAP-27 (ADCYAP1, P18509), peptide histidine isoleucineamide (PHI), peptide histidine methionineamide (PHM (VIP, P01282)) and peptide histidine valine (PHV (VIP, P01282)). “PACAP type II receptors” (VPAC₁ and VPAC₂ receptors) display comparable affinity for PACAP and VIP (VIP, P01282), whereas PACAP-27 (ADCYAP1, P18509) and PACAP-38 (ADCYAP1, P18509) are >100 fold more potent than VIP (VIP, P01282) as agonists of most isoforms of the PAC₁ receptor. However, one splice variant of the human PAC₁ receptor has been reported to respond to PACAP-38 (ADCYAP1, P18509), PACAP-27 (ADCYAP1, P18509) and VIP (VIP, P01282) with comparable affinity 1745. PG 99-465 1752 has been used as a selective VPAC₂ receptor antagonist in a number of physiological studies, but has been reported to have significant activity at VPAC₁ and PAC₁ receptors 1746. The selective PAC₁ receptor agonist maxadilan, was extracted from the salivary glands of sand flies (Lutzomyia longipalpis) and has no sequence homology to VIP (VIP, P01282) or PACAP 1753. Two deletion variants of maxadilan, M65 1758 and Max.d.4 1754 have been reported to be PAC₁ receptor antagonists, but these peptides have not been extensively characterised.

Nomenclature	VPAC1 receptor	VPAC2 receptor	PAC1 receptor
HGNC, UniProt	VIPR1, P32241	VIPR2, P41587	ADCYAP1R1, P41586
Principal transduction	Gs	Gs	Gs
Rank order of potency	VIP, PACAP-27, PACAP-38 >> GHRH (GHRH, P01286), PHI, secretin (SCT, P09683)	VIP, PACAP-38, PACAP-27 > PHI >> GHRH (GHRH, P01286), secretin (SCT, P09683)	PACAP-27, PACAP-38 >> VIP
Selective agonists (pKi)	[Ala11,22,28]VIP (8.1) 1755, [Lys15,Arg16,Leu27]VIP-(1–7)/GRF-(8–27)-NH2 (pEC50 8.3) 1751	Ro 25-1392 (8.0) 1760, Ro 25-1553 (pEC50 8.7) 1751, Ro 25-1553 (pEC50 8.3) 1750, Ro 25-1553 (pIC50 9.5) 1748, Ro 25-1553 (pIC50 8.8) 1750, Ro 25-1553 (pIC50 7.8) 1751	maxadilan (pEC50 10.3) 1746, maxadilan (pEC50 6.2) 1746
Selective antagonists (pKi)	PG 97-269 (pIC50 8.7) 1747, PG 97-269 (pIC50 8.7) 1750, PG 97-269 (pIC50 8.7) 1750, PG 97-269 (pIC50 8.0) 1746, PG 97-269 (pIC50 7.1) 1746	–	–
Radioligands (Kd)	[125I]PACAP-27 (Agonist), [125I]VIP (Agonist) (4x10-10 M) 1755	[125I]PACAP-27 (Agonist), [125I]VIP (Agonist) (7x10-10 M) 1755	[125I]PACAP-27 (Agonist) (8.7x10-10 M) 1756

Comments

Subtypes of PAC₁ receptors have been proposed based on tissue differences in the potencies of PACAP-27 (ADCYAP1, P18509) and PACAP-38 (ADCYAP1, P18509); these might result from differences in G protein coupling and second messenger mechanisms 1759, or from alternative splicing of PAC₁ receptor mRNA 1757.