P2Y

Overview: P2Y receptors (provisional nomenclature as agreed by NC-IUPHAR Subcommittee on P2Y Receptors, Abbracchio et al., 2003; 2006) 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	P2Y2	P2Y4	P2Y6
Ensembl ID	ENSG00000169860	ENSG00000175591	ENSG00000	ENSG00000171361
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
Selective agonists	2-MeSADP, ADPβS, MRS2365 (Bourdon et al., 2006)	UTPγS (Lazarowski et al., 1996), Ap4A (Castro et al., 1992), 2-thioUTP (El-Tayeb et al., 2006)	UTPγS (Lazarowski et al., 1996)	UDP, 3-phenacylUDP (PSB0474, El-Tayeb et al., 2006)
Selective antagonists	MRS2500 (8.8, Kim et al., 2003), MRS2279 (8.0, Waldo et al., 2002), MRS2179 (7.0, Boyer et al., 1996), PIT (6.8, Gao et al., 2004)	–	ATP (6.2, Kennedy et al., 2000)	MRS2578 (pIC50 7.4, Mamedova et al., 2004)
Probes	[3H]-MRS2279 (8 nM, Waldo et al., 2002), [35S]-ADPβS, [35S]-ATPαS, [35S]-dATPαS	–	–	–

Nomenclature	P2Y11	P2Y12	P2Y13	P2Y14
Other names	–	P2YADP, P2T	GPR86, GPR94, SP174	KIAAA00001, gpr105
Ensembl ID	ENSG00000176130	ENSG00000169313	ENSG00000181631	ENSG00000174944
Principal transduction	Gs, Gq/11	Gi/o	Gi/o	Gq/11
Rank order of potency	ATP > UTP	ADP >> ATP	ADP >> ATP	UDP-glucose
Selective agonists	ARC67085 (Communi et al., 1999), NAD+ (Moreschi et al., 2006), NAADP+ (Moreschi et al., 2008)	ADP, 2-MeSADP	–	MRS2690 (Ko et al., 2007)
Selective antagonists	NF157 (Ullmann et al., 2005)	ATP, ARL66096 (Humphries et al., 1995)	MRS2211 (Kim et al., 2005)	–

ARC69931MX shows selectivity for P2Y₁₂ and P2Y₁₃ receptors compared with other P2Y receptors (Takasaki et al., 2001; Marteau et al., 2003). NF157 also has antagonist activity at P2X₁ receptors (Ullmann et al., 2005). UDP has been reported to be an antagonist at the P2Y₁₄ receptor (Fricks et al., 2008).

A 7TM orphan receptor suggested to be a ‘P2Y₁₅’ receptor (Inbe et al., 2004) appears not to be a genuine nucleotide receptor (see Abbracchio et al., 2006), but rather responds to dicarboxylic acids (He et al., 2004). 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 (Webb et al., 1996a). In addition, human sources have yielded a clone with a preliminary identification of p2y5 (ENSG00000139679) and contradictory evidence of responses to ATP (King and Townsend-Nicholson, 2000; Webb et al., 1996b). This protein has recently been suggested to be receptor for lysophosphatidic acid (Pasternack et al., 2008; Yanagida et al., 2009), as has the clone clone termed p2y9 (LPA₄, ENSG00000147149, Noguchi et al., 2003). The clone p2y7 (ENSG00000196943), originally suggested to be a P2Y receptor (Akbar et al., 1996), has been shown to encode a leukotriene receptor (Yokomizo et al., 1997). 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 (Bogdanov et al., 1997). The p2y10 clone (ENSG00000078589) 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 (Castro et al., 1992). P2Y-like receptors have recently been described on mitochondria (Belous et al., 2004). CysLT₁ and CysLT₂ leukotriene receptors respond to nanomolar concentrations of UDP, although they are activated principally by leukotrienes C₄ and D₄ (Mellor et al., 2001; 2003;); Human (ENSG00000144230) and rat GPR17, which are structurally related to CysLT and P2Y receptors, are also activated by leukotrienes as well as UDP and UDP-glucose (Ciana et al., 2006). Activity at the rat GPR17 is inhibited by submicromolar concentrations of MRS2179 and ARL69931 (Ciana et al., 2006).

Glossary

Abbreviations:

2-MeSADP

2-methylthio-adenosine-5′-diphosphate

2-MeSATP

2-methylthio-adenosine-5′-triphosphate

ARC67085

2-propylthio-βγ-dichloromethylene-ATP

ARC69931MX

N⁶-(2-methylthioethyl)-2-(3,3,3-trifluoropropylthio)-βγ-dichloromethylene-ATP, also known as cangrelor

ARL66096

2-propylthio-βγ-difluoromethylene ATP (previously FPL66096)

ATPγS

adenosine 5′-(3-thio)triphosphate

MRS2179

N⁶-methyl-2′-deoxyadenosine-3′,5′-bisphosphate

MRS2211

pyridoxal-5′-phosphate-6-azo (2-chloro-5-nitrophenyl)-2,4-disulfonate

MRS2279

2-chloro-N⁶-methyl-(N)-methanocarba-2′-deoxyadenosine-3′,5′-bisphosphate

MRS2365

(N)-methanocarba-2-MeSADP

MRS2500

N⁶-methyl-(N)-methanocarba-2′-deoxyadenosine-3′,5-bisphosphate

MRS2578

N,N′′-1,4-butanediyl bis(N′-[3-isothiocynatophenyl)] thiourea

MRS2690

2-thiouridine-5’-diphosphoglucose

NF157

8,8′-[carbonylbis[imino-3,1-phenylenecarbonylimino(4-fluoro-3,1-phenylene)carbonylimino]]bis-1,3,5-naphthalene trisulfonic acid hexasodium salt

PIT

2,2′-pyridylisatogen tosylate

Further Reading

Abbracchio MP, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, Miras-Portugal MT et al. (2003). Characterization of the UDP-glucose receptor (re-named here the P2Y₁₄ receptor) adds diversity to the P2Y receptor family. Trends Pharmacol Sci24: 52–55.

Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C et al. (2006). International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy. Pharmacol Rev58: 281–341.

Burnstock G (2007). Purine and pyrimidine receptors. Cell Mol Life Sci64: 1471–1483.

Burnstock G (2008). Purinergic signalling and disorders of the central nervous system. Nat Rev Drug Discovery7: 575–590.

Erlinge D, Burnstock G (2008). P2 receptors in cardiovascular regulation and disease. Purinergic Signal4: 1–20.

Jacobson KA, Ivanov AA, de Castro S, Harden TK, Ko H (2009). Development of selective agonists and antagonists of P2Y receptors. Purinergic Signal5: 75–89.