Overview: Chemokine receptors (nomenclature agreed by NC-IUPHAR Subcommittee on Chemokine Receptors, Murphy et al., 2000; Murphy, 2002) comprise a large subfamily of 7TM receptors activated by one or more of the chemokines, a large family of small cytokines typically possessing chemotactic activity for leukocytes.
Chemokines 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= 16) 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. Listed are those human agonists with EC50 values <50 nM in either Ca2+ flux or chemotaxis assays at human recombinant 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 HIV-encoded non-chemokine ligands have also been identified for chemokine receptors. Many chemokine receptors function as HIV co-receptors, and at least two, CCR5 and CXCR4, play prominent roles in pathogenesis. The tables include both standard chemokine names (Zlotnik and Yoshie, 2000) and the most commonly used synonyms. Numerical data quoted are typically pKi or pIC50 values from radioligand binding to heterologously expressed receptors.
| Nomenclature | CCR1 | CCR2 | CCR3 | CCR4 | CCR5 |
|---|---|---|---|---|---|
| Other names | CKR1, CC CK1, CC CKR1, MIP-1αR, MIP-1α/RANTES | CKR2, CC CK2, CC CKR2, MCP-1 | CKR3, CC CK3, CC CKR3 | CKR4, CC CK4, CC CKR4 | CKR5, CC CK5, CC CKR5, CHEMR13 |
| Ensembl ID | ENSG00000163823 | ENSG00000121807 | ENSG00000183625 | ENSG00000183813 | ENSG00000160791 |
| Principal transduction | Gi/o | Gi/o | Gi/o | Gi/o | Gi/o |
| Agonists | CCL3 (MIP-1α), CCL5 (RANTES), CCL7 (MCP-3), CCL8 (MCP-2), CCL13 (MCP-4), CCL14a (HCC-1), CCL15 (HCC-2), CCL23 (MPIF-1) | CCL2 (MCP-1), CCL7 (MCP-3), CCL8 (MCP-2), CCL13 (MCP-4), CCL16 (HCC-4), HIV-1 Tat | CCL11 (eotaxin), CCL5 (RANTES), CCL7 (MCP-3), CCL8 (MCP-2), CCL13 (MCP-4), CCL15 (HCC-2), CCL24 (eotaxin-2), CCL26 (eotaxin-3), CCL28 (MEC), HIV-1 Tat | CCL22 (MDC), CCL17 (TARC), HHV8 vMIP-III, | CCL3 (MIP-1α), CCL4 (MIP-1β), CCL5 (RANTES), CCL8 (MCP-2), CCL11 (eotaxin), CCL14a (HCC-1), CCL16 (HCC-4), R5 HIV-1 gp120 |
| Selective agonists | CCL15 (HCC-2), CCL23 (MPIF-1) | CCL2 (MCP-1) | CCL11 (eotaxin), CCL24 (eotaxin-2), CCL26 (eotaxin-3), | CCL22 (MDC), CCL17 (TARC) | MIP-1β, R5-HIV gp120 |
| Selective antagonists | BX471 (8.3-9), 2b-1 (8.7), UCB35625 (8.0), CP-481,715 (8.0), CCL4 (MIP-1β) | CCL11 (eotaxin), CCL26 (eotaxin-3), GSK Compound 34 (7.6) | Banyu Compound 1b (8.6), SB328437 (8.4), BMS Compound 87b (8.1), CXCL10 (IP10), CXCL9 (Mig), CXCL11 (I-TAC) | – | TAK779 (9.0), CCL7 (MCP-3), SCH C, SCH D, MRK-1, E913 (8.7), maraviroc, aplaviroc |
| Probes | [125I]-MIP-1α, [125I]-RANTES, [125I]-MCP-3 | [125I]-MCP-1, [125I]-MCP-3 | [125I]-RANTES, [125I]-eotaxin, [125I]-MCP-3 | [125I]-TARC, [125I]-CTACK/CCL27 | [125I]-RANTES, [125I]-MCP-2, [125I]-MIP-1α, [125I]-MIP-1β |
| Nomenclature | CCR6 | CCR7 | CCR8 | CCR9 | CCR10 |
|---|---|---|---|---|---|
| Other names | GPR-CY4, CKR-L3, STRL-22, DRY-6, DCR2, BN-1, GPR29 | EBI-1, BLR-2 | TER1, CKR-L1, GPR-CY6, ChemR1 | GPR 9-6 | GPR-2 |
| Ensembl ID | ENSG00000153467 | ENSG00000126353 | ENSG00000179934 | ENSG00000173585 | ENSG00000184451 |
| Principal transduction | Gi/o | Gi/o | Gi/o | Gi/o | Gi/o |
| Agonists | CCL20 (LARC), HBD2 | CCL19 (ELC, MIP-3β), CCL21 (SLC) | CCL1 (I-309), CCL4 (MIP-1β), CCL16 (HCC-4), CCL17 (TARC), HHV8 vMIP-I | CCL25 (TECK) | CCL27 (eskine, ALP, CTACK), CCL28 (MEC) |
| Selective agonists | LARC, HBD2 | ELC, SLC | I-309 | TECK | Eskine, MEC |
| Selective antagonists | – | – | MCV MC148R (vMCC-I) | – | – |
| Probes | [125I]-LARC | [125I]-ELC, [125I]-SLC | [125I]-I309 | [125I]-TECK | – |
| Nomenclature | CXCR1 | CXCR2 | CXCR3 | CXCR4 | CXCR5 | CXCR6 |
|---|---|---|---|---|---|---|
| Other names | IL8RA, IL-8 receptor type I, IL-8 receptor α | IL8RB, IL-8 receptor type II, IL-8 receptor β | IP10/Mig R, GPR9 | HUMSTSR, LESTR, fusin, HM89, LCR1 | BLR-1, MDR15 | STRL-33, BONZO, TYMSTR |
| Ensembl ID | ENSG00000163464 | ENSG00000180871 | ENSG00000186810 | ENSG00000121966 | ENSG00000160683 | ENSG00000172215 |
| Principal transduction | Gi/o | Gi/o | Gi/o | Gi/o | Gi/o | Gi/o |
| Agonists | CXCL6 (GCP-2), CXCL8 (IL-8), cytokine domain of tyrosyl tRNA synthetase | CXCL1 (GROα), CXCL2 (GROβ), CXCL3 (GROγ), CXCL5 (ENA78), CXCL6 (GCP-2), CXCL7 (NAP-2), CXCL8 (IL-8), HCMV UL146 (vCXC-1) | CXCL9 (Mig), CXCL10 (IP10), CXCL11 (I-TAC) | CXCL12α (SDF-1α), CXCL12β (SDF-1β) | CXCL13 (BLC, BCA-1) | CXCL16 (SR-PSOX) |
| Selective agonists | – | GROα, GROγ, GROβ, NAP-2, ENA78 | IP10, MIG, I-TAC | SDF-1α, SDF-1β, X4-HIV gp120 | BLC | CXCL16 |
| Selective antagonists | – | SB225002 (7.7) | eotaxin, MCP-3 | AMD3100, HIV-1 Tat, T134, ALX41-4C | – | – |
| Probes | [125I]-IL8 | [125I]-IL8, [125I]-GROα, [125I]-NAP-2, [125I]-ENA78 | [125I]-IP10, [125I]-I-TAC/CXCL11 | [125I]-SDF-1 | – | [125I]-CXCL16 |
CXCR1 and CXCR2 also couple to phospholipase C when co-transfected with members of the Gq/11 family of G proteins. Mouse CXCR2 binds iodinated mouse KC and mouse MIP-2 with high affinity (mouse KC and MIP-2 are homologues of human GRO chemokines), but shows low affinity for human IL-8.
| Nomenclature | CX3CR1 | XCR1 |
|---|---|---|
| Other names | CMKBRL1, V28 | GPR5 |
| Ensembl ID | ENSG00000168329 | ENSG00000173578 |
| Principal transduction | Gi/o | Gi/o |
| Agonists | CX3CL1 (Fractalkine) | XCL1 α and β (Lymphotactin α and β) |
| Selective agonists | Fractalkine | Lymphotactin |
| Probes | [125I]-Fractalkine | SEAP-XCL1 |
Three human 7TM chemokine binding proteins have been identified that lack a known signalling function: D6 (ENSG00000144648), which binds multiple CC chemokines; a molecule previously inappropriately named CCR11 and now known as CCX CKR or the human homologue of the bovine gustatory receptor PPAR1 (ENSG00000118519, ENSG00000129048), which binds ELC, SLC and TECK; and Duffy, a highly promiscuous CC and CXC chemokine binding protein expressed mainly on erythrocytes. CXCR7 (former aliases: RDC1, CMKOR1 and GPR159, ENSG00000144476) binds CXCL11 and CXCL12 with high affinity, and is expressed in all four cardiac valves and by marginal zone B cells in mammals. Mice lacking this receptor undergo perinatal mortality because of valvular stenosis. Work in zebrafish has identified a role for a highly conserved CXCR7 homologue in shaping CXCL12 gradients, which guide primordial germ cell migration. Whether this is how it works in mammals, or whether there is, in addition, a signal transduction function for CXCR7 has not yet been fully resolved. Thus, the name CXCR7, though widely used in the field, has not yet been endorsed officially by IUPHAR. Specific chemokine receptors facilitate cell entry by microbes, such as Plasmodium vivax, HIV-1 and the poxvirus myxoma virus. Virally encoded chemokine receptors are known (e.g. US28, a homologue of CCR1 from human cytomegalovirus and ECRF3, a homologue of CXCR2 from Herpesvirus saimiri), 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), MCP-1 (CCL2), MIP-1α (CCL3), MIP-1β (CCL4), RANTES (CCL5), MCP-3 (CCL7), MCP-2 (CCL8), eotaxin (CCL11), MCP-4 (CCL13), HCC-1 (CCL14), Lkn-1/HCC-2 (CCL15), TARC (CCL17), ELC (CCL19), LARC (CCL20), SLC (CCL21), MDC (CCL22), MPIF-1 (CCL23), eotaxin-2 (CCL24), TECK (CCL25), eotaxin (CCL26), eskine/CTACK (CCL27) and MEC (CCL28). The CXC chemokine family (CXCL1–16) includes GROα (CXCL1), GROβ (CXCL2), GROγ (CXCL3), platelet factor 4 (CXCL4), ENA78 (CXCL5), GCP-2 (CXCL6), NAP-2 (CXCL7), IL-8 (CXCL8), MIG (CXCL9), IP10 (CXCL10), I-TAC (CXCL11), SDF-1 (CXCL12), BLC (CXCL13), BRAK (CXCL14), mouse lungkine (CXCL15) and SR-PSOX (CXCL16). The CX3C chemokine (CX3CL1) is also known as fractalkine (neurotactin in the mouse). Like CXCL16, and unlike other chemokines, CX3CL1 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) is also known as lymphotactin. The non-chemokine family includes the cytokine domain of tyrosyl-tRNA synthetase, HBD2, HIV gp120 and HIV Tat. 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 AMD3100 (Plerixifor, Mozibil from Genzyme) for hematopoietic stem cell mobilization with G-CSF in patients undergoing transplantation in the context of chemotherapy for lymphoma and multiple myeloma.
Glossary
Abbreviations:
- BLC
B-lymphocyte chemokine
- ELC
Epstein–Barr virus-induced receptor ligand chemokine
- ENA78
epithelial cell-derived neutrophil-activating factor-78 amino acids
- GCP-2
granulocyte chemoattractant protein 2
- HBD2
human β defensin 2
- HCC
hemofiltrate CC chemokine
- I-TAC
interferon-inducible T-cell α chemoattractant
- IL-8
interleukin 8
- IP-10
γ-interferon-inducible protein 10
- LARC
liver and activation-related chemokine (CCL20)
- MCP
monocyte chemoattractant protein
- MDC
macrophage-derived chemokine
- MEC
mucosa expressed chemokine
- MIG
monokine-induced by γ-interferon
- MIP
macrophage inflammatory protein
- MPIF-1
myeloid progenitor inhibitory factor 1
- NAP-2
neutrophil-activating peptide 2
- RANTES
regulated on activation normal T cell expressed and secreted
- SDF
stromal cell-derived factor
- SEAP
secreted alkaline phosphatase
- SLC
secondary lymphoid tissue chemokine
- TARC
T-cell and activation-related chemokine
- TECK
thymus-expressed chemokine
Further Reading
Ali S, O'Boyle G, Mellor P, Kirby JA (2007). An apparent paradox: chemokine receptor agonists can be used for anti-inflammatory therapy. Mol Immunol44: 1477–1482.
Allen SJ, Crown SE, Handel TM (2007). Chemokine: receptor structure, interactions, and antagonism. Annu Rev Immunol25: 787–820.
Bonecchi R, Galliera E, Borroni EM, Corsi MM, Locati M, Mantovani A (2009). Chemokines and chemokine receptors: an overview. Front Biosci14: 540–551.
Horuk R (2009). Chemokine receptor antagonists: overcoming developmental hurdles. Nat Rev Drug Discov8: 23–33.
Mellado M, Carrasco YR (2008). Imaging techniques: new insights into chemokine/chemokine receptor biology at the immune system. Pharmacol Ther119: 24–32.
Mortier A, Van DJ, Proost P (2008). Regulation of chemokine activity by posttranslational modification. Pharmacol Ther120: 197–217.
Murphy PM (2002). International Union of Pharmacology. XXX. Update on chemokine receptor nomenclature. Pharmacol Rev54: 227–229.
Murphy PM, Baggiolini M, Charo IF, Hebert CA, Horuk R, Matsushima K et al. (2000). International Union of Pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol Rev52: 145–176.
Ruffini PA, Morandi P, Cabioglu N, Altundag K, Cristofanilli M (2007). Manipulating the chemokine-chemokine receptor network to treat cancer. Cancer109: 2392–2404.
Salanga CL, O'Hayre M, Handel T (2009). Modulation of chemokine receptor activity through dimerization and crosstalk. Cell Mol Life Sci66: 1370–1386.
Tsibris AM, Kuritzkes DR (2007). Chemokine antagonists as therapeutics: focus on HIV-1. Annu Rev Med58: 445–459.
Wang J, Norcross M (2008). Dimerization of chemokine receptors in living cells: key to receptor function and novel targets for therapy. Drug Discov Today13: 625–632.
Ward SG, Marelli-Berg FM (2009). Mechanisms of chemokine and antigen-dependent T-lymphocyte navigation. Biochem J418: 13–27.
Zlotnik A, Yoshie O (2000). Chemokines: a new classification system and their role in immunity. Immunity12: 121–127.