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Chemokine Receptors

Chemokines are a family of low molecular weight secreted proteins that act as leukocyte specific chemoattractants, although they may have additional immunological and non-immunological activities. The greater than 40 known chemokines can be grouped into subfamilies based on structural and genetic considerations. All chemokines (except for lymphotactin) have at least four cysteines in nearly invariant positions. In one major subfamily (CXC or α), the two conserved cysteines in the N-terminal domain are separated by a single amino acid, while in the other major subfamily (CC or β) these two cysteines are adjacent. The other two subfamilies, named C (or γ) and CX3C, are comparatively minor, having only two and one known member(s) in man, respectively. C chemokines are characterized by a single cysteine in the N-terminal domain, and the CX₃C chemokine (known as ‘fractalkine’) has three amino acids interposed between its two amino terminal cysteines.

The genes that encode chemokines tend to cluster with a large cluster of CXC chemokine genes mapping to human chromosome 4q13 and a cluster of CC chemokine genes found on 17q11.1-12. With the rapid pace of discovery of novel chemokines over the course of the last few years, there have been a significant number of reports identifying the same gene, which is typically assigned a different name by the individual investigators. Recently, a standard nomenclature system has been developed and approved by the IUIS/WHO nomenclature committee. In this scheme, the chemokines are named CCL1-28 (C-C chemokine members), CXCL1-16 (CXC chemokine members), CX₃CL1 (fractalkine) and XCL1 and 2 (lymphotactin and SCM-1β).

The basis for leukocyte-specific chemoattraction lies in restricted expression of chemokine receptors (CKR) that are seven transmembrane spanning (7TM) G protein-coupled receptors. So far, six CXC and 11 CC chemokine receptors have been cloned and designated CXCR1-6 and CCR1-11, respectively. In addition, one C and one CX₃C chemokine receptor subtypes have been cloned. Three non-signaling mammalian 7TM chemokine binding proteins have also been identified: the Duffy Antigen Receptor for Chemokines (DARC) that binds both CC and CXC chemokines with high affinity and serves as the receptor for Plasmodium vivax, D6 and CCX CKR. These molecules are thought to function as decoy receptors or chemokine scavengers, negatively regulating chemokine action. Like chemokine genes, chemokine receptor genes also tend to cluster, with a major locus occurring at 3p21.31-32. Most chemokine receptors are coupled through pertussis toxin-sensitive Ga_i proteins, although there is considerable evidence for additional Ga_q coupling in many cases. In addition to the mammalian host chemokine system, many mammalian DNA viruses have also been identified that encode chemokines, functional 7TM chemokine receptors and chemokine receptor-like proteins, presumably pirated from their hosts. Secreted viral chemokine binding proteins with unique structures have also been identified. Finally, some viral proteins function as chemokine mimics. The most notable example is the envelope glycoprotein gp120 of HIV that is able to bind one or more chemokine receptors as an essential step in the cell entry process.

A conundrum in chemokine physiology is the fact that when most chemokine receptors are expressed in heterologous cells, they are found to bind several chemokines with high affinities (K_d <5 nM). Similarly, many individual chemokines bind to multiple receptors. This ligand/receptor promiscuity has led to the suggestion that individual chemokines or individual receptors might not play unique roles in leukocyte physiology or disease. There are however a select number of chemokine receptors that are now recognized to bind a single dedicated ligand. These primarily represent receptors and ligands mediating ‘homeostatic’ functions related to lymphoid organ development and cell population. There is growing evidence that a large number of chemokines may, however, function outside of the simple trafficking paradigm. While classical characterization of chemokine function has centered around cell migration, a large number of chemokines (of all subfamilies) appear to be highly expressed and trigger complex signaling in cells and tissue microenvironments where migration is not a relevant or necessary functionality, and the signaling initiated is peripheral to the migratory phenotype. In addition, chemokine redundancy predicted by in vitro binding patterns appears not to be relevant in vivo. Mice engineered by targeted gene disruption to lack single chemokines or receptors have profoundly abnormal phenotypes indicating that chemokines cannot compensate completely for each other. The basis for this specificity is likely to lie in the spatio-temporal patterns of expression that appear to be unique for each chemokine, in addition to a high degree of divergence in signaling cascades stimulated following receptor ligation.

The Tables below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

Receptor	CXCR₁	CXCR₂	CXCR₃	CXCR₄	CXCR₅
Alternate Names	IL-8RA IL-8R Type 1	IL-8RB IL-8R Type 2		LESTR HUMSTR Fusin	BLR-1 MDR15
Structural Information	350 aa (human)	360 aa (human)	368 aa (human)	352 aa (human)	372 aa (human)
Selective Agonists	IL-8 (I1645) GCP-2 (RAB0134)	IL-8 (I1645) GRO-α (G0657) GRO-β (G7909) GRO-γ (G7784) NAP-2 (N214) GCP-2 (RAB0134) ENA-78	IP-10 (I3400) MIG (M252) I-TAC (I5528) vMIP-II	SDF-1α (PBSF) (S190) (Co-receptor with CD4, for gp120 from T-cell-tropic HIV-1) vMIP-II	BCA-1 (B2929) CD4 (for gp120 from T-cell-tropic HIV-1)
Signal Transduction Mechanisms	G_i(PI hydrolysis, PI3K) (cAMP modulation)	G_i (PI hydrolysis, PI3K) (cAMP modulation)	G_i (PI hydrolysis, PI3K) (cAMP modulation)	G_i (PI hydrolysis, PI3K) (cAMP modulation)	G_i (PI hydrolysis, PI3K) (cAMP modulation)
Radioligands of Choice	[¹²⁵I]-IL-8	[¹²⁵I]-GRO-α	[¹²⁵I]-IP-10	[¹²⁵I]-SDF-1α	[¹²⁵I]-BCA-1
Tissue Expression	Neutrophils, T cells, eosinohpils, NK, other leukocytes and endothelial cells	Leukocytes, endothelial cells	Activated T cells, NK cells, monocytes	Peripheral blood leukocytes, spleen, thymus, spinal cord, heart, placenta, lung, liver, skeletal muscle, kidney, pancreas, cerebellum, cerebral cortex and medulla, microglia, astrocytes, coronary artery and umbilical cord endothelial cells	Naïve T cells, B cells, endothelial cells, osteoclasts
Physiological Function	Cell migration	Migration, angiogenesis	Cell migration	Hemopoiesis, vascularization of intestinal tract, cardiac ventricular septum formation, CD4- HIV-2 and -HIV-1 X4 strain co-receptor function	Cell migration and adhesion
Disease Relevance	Pulmonary inflammation	Inflammation, tumor growth, arthritis	Autoimmune disease	WHIM syndrome	Inflammation, germinal center and follicular organization

Receptor	CXCR₆	CCR₁	CCR₂	CCR₃	CCR₄
Alternate Names	Bonzo STRL33
Structural Information	340 aa (human)	355 aa (human)	374 aa (human)	355 aa (human)	360 aa (human)
Selective Agonists	CXCL16 (SRP3023)	MIP-1α (h) (M6292) MIP-1α (m) (M6167) MCP-2 (h) (RAB0079) MCP-2 (m) (SRP4226) MCP-3 (M8543) MCP-4 (M246) RANTES (h) (R6267) RANTES (m) (R2274) HCC-1 (H0656) HCC-2 HCC-4 (RAB0049) MIP-3 (SRP3116) muMCP-5 (M263) vMIP-II	MCP-1 (h) (M6667) MCP-1 (r) (M208) MCP-2 (h) (RAB0079) MCP-2 (m) (SRP4226) MCP-3 (M8543) MCP-4 (M246) HCC-4 (RAB0049) vMIP-II	Eotaxin (h) Eotaxin (m) Eotaxin-2 (h) (SRP4497) Eoxtain-2 (m) (E9152) Eotaxin-3 (h) (E8399) RANTES (h) (R6267) RANTES (m) (R2274) MCP-2 (h) (RAB0079) MCP-2 (m) (SRP4226) MCP-3 (M8543) MCP-4 (M246) HCC-2 vMIP-II	TARC (h) (SRP4333) TARC (m) (T9694) MDC (M251) vMIP-II
Signal Transduction Mechanisms	G_i (PI hydrolysis, PI3K) (cAMP modulation)	G_i (PI hydrolysis, PI3K) (cAMP modulation)	G_i (PI hydrolysis, PI3K) (cAMP modulation)	G_i (PI hydrolysis, PI3K) (cAMP modulation)	G_i (PI hydrolysis, PI3K) (cAMP modulation)
Radioligands of Choice	[¹²⁵I]-CXCL16	[¹²⁵I]-MIP-1α	[¹²⁵I]-MCP-1	[¹²⁵I]-Eotaxin	[¹²⁵I]-TARC
Tissue Expression	Lymphoid, activated T cells	Hematopoietic cells	Monocytes, T cells, neuronal	Eosinopils, Th0, Th2 cells, mast cells, basophils, microglia	CD4+ lymphocytes, NK cells thymus, CLA+ T cells, platelets, monocytes, spleen, brain and coronary artery endothelial cells
Physiological Function	Receptor for SIV, HIV-2, m-tropic HIV-1	Cell migration, neuronal signaling	Migration, adhesion	Migration, HIV-1-CD4 co-receptor activity	Migration, HIV-2 binding, CNS neuronal survival
Disease Relevance	HIV, inflammation	Autoimmune (renal, hepatic), inflammation	Inflammation, HIV, Atherosclerosis, dermatoses, pulmonary fibrosis	Eosinophilic inflammation in gut, asthma, atopic dermatitis	Allergic inflammation, modulate susceptibility to endotoxic shock in mice

Receptor	CCR₅	CCR₆	CCR₇	CCR₈	CCR₉
Alternate Names		GPR-CY4 CKRL-3 STRL-22	EBI1 BLR2	GPR-CY6 TER1 CKR-L1	GPR-9-6
Structural Information	352 aa (human)	374 aa (human)	378 aa (human)	355 aa (human)	348 aa (human)
Selective Agonists	MIP-1α (h) (M6292) MIP-1α (m) (M6167) MIP-1β (h) (M6417) MIP-1β (m) (M6542) RANTES (h) (R6267) RANTES (m) (R2274) (Co-receptor with CD4 for gp120 from M cell-tropic HIV-1) CCF18 (SRP3225) HCC-1 (H0656) HCC-4 (RAB0049) vMIP-II	MIP-3α (M249) (LARC, Exodus-1) 6Ckine (C0845)	MIP-3β (M3552) (ELC, Exodus-3)	I309 (I152) vMIP-II vMIP-I	TECK/CK β15 (h) (T9569) TECK (m) (T9444)
Signal Transduction Mechanisms	G_i (PI hydrolysis, PI3K) (cAMP modulation)	G_i (cAMP modulation) (PI hydrolysis, PI3K)	G_i (PI hydrolysis, PI3K)	G_i (PI hydrolysis, PI3K)	G_i (PI hydrolysis, PI3K)
Radioligands of Choice	[¹²⁵I]-MIP-1β	[¹²⁵I]-MIP-3α	[¹²⁵I]-MIP-3β	[¹²⁵I]-I309	[¹²⁵I]-TECK
Tissue Expression	Pro-myelocytic cells, macrophages, T cells, neuronal progenitor cells	Spleen, lymph node, appendix, fetal liver, T and B cells	Lymphoid tissue, T and B cells	Monocytes, Th2 cells, granulocytes	Thymus, some in lymph nodes and spleen
Physiological Function	Hematopoietic cell expansion, m-tropic HIV-1-CD4 co-receptor function	Migration	T and B cell homing, migration, upregulated by EBV in B cells and HSV 6 and 7 in T cells	Cell migration, Anti-apoptosis of thymic cells, CD4-HIV-1 co-receptor	Cell migration, CD4-HIV co-receptor
Disease Relevance	HIV infection	Homing of T cells in psoriasis allergic asthma; pancreatic cancer cell invasion	Herpesvirus, autoimmunity	Allergic inflammation	Gut inflammation, HIV

Receptor	CCR₁₀	XCR₁	CX₃CR1	DARC	D6
Alternate Names	GPR2	GPR5	V28 fractalkine receptor	Duffy antigen
Structural Information	360 aa (human)	332 aa (human)	355 aa (human)	338 aa (human)	Not Known
Selective Agonists	CTACK/Eskine (C8365) MEC (h) (SRP3112) MEC (m) (SRP3223) vMIP-II	Lymphotactin/XCL1 (h) (L9788) Lymphotactin (m) (L6516) vMIP-II	CX₃C chemokine Fractalkine (Chemokine domain: (h) (F1300), (m) (F2302), (r) (F8551); Extracellular domain: (h) (F135), (m) (F7551), (r))	IL-8 (I1645) GRO-α (G0657) NAP-2 (N214) MCP-1 (h) (M6667) MCP-1 (r) (M208) RANTES (h) (R6267) RANTES (m) (R2274), Plasmodium vivax Plasmodium knowlesi	MCP-1 (h) (M6667) MCP-1 (r) (M208) MCP-2 (h) (RAB0079) MCP-2 (m) (SRP4226) MCP-3 (M8543) MCP-4 (M246) mMCP-5 (M263) HCC-1 (H0656) MIP-1α (h) (M6292) MIP-1α (m) (M6167) MIP-1β (h) (M6417) MIP-1β (m) (M6542) RANTES (h) (R6267) RANTES (m) (R2274) Eotaxin (h) Eotaxin (m)
Signal Transduction Mechanisms	G_i (PI hydrolysis, PI3K)	G_i (PI hydrolysis, PI3K)	G_i (cAMP modulation)	Not Known	Not Known
Radioligands of Choice	[¹²⁵I]-CTACK/ESkine	[¹²⁵I]-lymphotactin/XCL1	[¹²⁵I]-Fractalkine	[¹²⁵I]-IL-8 [¹²⁵I]-RANTES	[¹²⁵I]-MIP-1β
Tissue Expression	Testis, small intestine fetal lung and kidney, widespread expression	Lymphoid	Lymphoid, cardiovascular, smooth muscle and neuronal	Adult kidney, spleen and fetal liver postcapillary venules, erythroid cells	Placenta, fetal liver, lung, endothelial cells of afferent lymphatics in dermis tonsilar lymphatic sinuses, lymphatics in mucosa of small and large intestine and appendix; also found in some malignant vascular tumors
Physiological Function	T cell migration	Migration	Cell adhesion, migration and HIV co-receptor function with CD4, anti-apoptotic	Non-specific receptor for chemokines, Plasmodium vivax and P. knowlesi	Receptor for C-C type chemokines
Disease Relevance	Lymphocyte homing to skin	Not Known	Atherogenesis, cardiovascular disease	Duffy negative phenotype more resistant to malaria infection	Not Known

Receptor	CCX-CKR	ECRF3 (Herpesvirus saimiri)	US28 (Cytomegalovirus)	KSHV receptor	U12/UL33 family	U51 family (HHV-6 and -7) UL78 (HCMV)
Alternate Names				ORF-74
Structural Information	350 aa (human)	321 aa (Herpesvirus saimiri)	354 aa (human cytomegalovirus)	342 aa (Kaposi’s sarcoma-associated herpesvirus/human herpesvirus 8)	333 aa (U12; Human herpesvirus-7) 412 aah (UL33; hCMV – orphan receptor)	301 aa (431 aa UL78)
Selective Agonists	TECK/CK b15 (h) (T9569) TECK (m) (T9444) 6Ckine (C0845) MIP-3β (M3552)	IL-8 (I1645) GRO-α (G0657) NAP-2 (N214)	MIP-1α (h) (M6292) MIP-1α (m) (M6167) MIP-1β (h) (M6417) MIP-1β (m) (M6542) MCP-1 (h) (M6667) MCP-1 (r) (M208) RANTES (h) (R6267) RANTES (m) (R2274) Fractalkine (Chemokine domain: (h) (F1300), (m) (F2302), (r) (F8551); Extracellular domain: (h) (F135), (m) (F7551), (r)) Eotaxin (h) Eotaxin (m) MCP-3 (M8543) vMIP-II	IL-8 (I1645) NAP-2 (N214) GRO-α (G0657) ENA-78 SDF-1α (h) (S190) SDF-1α (m) (S5816) RANTES (h) (R6267) RANTES (m) (R2274) I309 (I152) vMIP-II	MIP-1α (h) (M6292) MIP-1α (m) (M6167) MIP-1β (h) (M6417) MIP-1β (m) (M6542) RANTES (h) (R6267) RANTES (m) (R2274) MIP-3β (M3552); HHV-7 encoded (U12 only)	RANTES (h) (R6267) RANTES (m) (R2274) Eotaxin (h) Eotaxin (m) MCP-1 (h) (M6667) MCP-1 (r) (M208) MCP-3 (M8543) MCP-4 (M246) vMIP-II
Signal Transduction Mechanisms	Not Known	G_i (cAMP modulation) G_q/11 (increase IP₃/DAG)	G_i (cAMP modulation) G_q/11 (increase IP₃/DAG)	G_i (cAMP modulation) (PI hydrolysis)	G_i (PI hydrolysis)	Not Known
Radioligands of Choice	[¹²⁵I]-TECK [¹²⁵I]-MIP-3β	[¹²⁵I]-IL-8	[¹²⁵I]-MIP-1α	[¹²⁵I]-IL-8	[¹²⁵I]-MIP-1α [¹²⁵I]-RANTES	[¹²⁵I]-RANTES [¹²⁵I]-Eotaxin
Tissue Expression	Heart, lower expression in lung, pancreas, spleen, small intestine	Adult kidney, spleen and fetal liver postcapillary venules, erythroid cells	Placenta, fetal liver, lung, endothelial cells of afferent lymphatics in dermis tonsilar lymphatic sinuses lymphatics in mucosa of small and large intestine and appendix. Also found in some malignant vascular tumors.	Leukocyte, smooth muscle cell, endothelial cell infection	Monocytes, macrophages, CD4 T cells, smooth muscle cell, migration, dendritic cells, oligodendrocytes, epithelium	Lymphoid, dendritic and oligodendritic cells, smooth muscle, epithelium
Physiological Function	Migration	Non-specific receptor for chemokines, Plasmodium vivax and P. knowlesi	Receptor for C-C type chemokines	Modulates cell migration, affects cell cycling and signal transduction, angioproliferative	Constitutive cell signal transduction, cell cycling	Immune modulatory, proliferative
Disease Relevance	Not Known	Duffy negative phenotype more resistant to malaria infection	Latent infection, immune-suppression after organ transplantation	Herpesvirsus inflammation, vascular disease, Kaposi’s sarcoma, neoplasia	Herpesvirsus, AIDS progression vascular disease (sclerosis, restenosis)	Herpesvirsus

Abbreviations

6-Ckine/SLC/exodus-2: (CCL21)
BCA-1: B-Lymphocyte Chemoattractant (CXCL13)
CCF18: MIP-1γ (Ccl 9)
CTACK/ESkine: Cutaneous T cell-attracting chemokine (CCL27)
ELC/MIP-3b/exodus 3: (CCL19)
ENA-78: Epithelial Neutrophil Activating Peptide-78 (CXCL5)
Eotaxin: (CCL11)
Fractalkine: (CX3CL1)
GCP-2: Granulocyte Chemotactic Protein-2 (CXCL6)
GRO-α: Growth-Related Oncogene α (CXCL1)
GRO-β: Growth-Related Oncogene β (CXCL2)
GRO-γ: Growth-Related Oncogene γ (CXCL3)
HCC-1/CKβ1/MCIF: Hemofiltrate CC chemokine-1 (CCL14)
HCC-1: Hemofiltrate CC chemokine-1
HCC-2/MIP-5/Lkn-1: Hemofiltrate CC chemokine-2 (CCL15)
HCC-4/LCC-1/CKβ12: Hemofiltrate CC chemokine-4 (CCL16)
I309: (CCL1)
IL-8: Interleukin-8 (CXCL8)
IP-10: Interferon-γ-Inducible Protein-10 (CXCL10)
I-TAC: IFN-Inducible T-cell α-chemoattractant (CXCL11)
MCP-1: Monocyte Chemotactic Protein-1 (CCL2)
MCP-2: Monocyte Chemotactic Protein-2 (CCL8)
MCP-3: Monocyte Chemotactic Protein-3 (CCL7)
MCP-4: Monocyte Chemotactic Protein-4 (CCL13)
MDC: Macrophage-derived Chemokine (CCL22)
MEC: (CCL28)
MIG: Monokine induced by interferon-γ (CXCL9)
MIP-1α: Macrophage Inflammatory Protein-1α (CCL3)
MIP-1β: Macrophage Inflammatory Protein-1β (CCL4)
MIP-3/Ckβ-8: Macrophage Inflammatory Protein-3 (CCL23)
MIP-3α: Macrophage Inflammatory Protein-3α (CCL20)
MIP-3β: Macrophage Inflammatory Protein-3β (CCL19)
mMCP-5: (CCL12)
muMCP-5: (CCL12)
NAP-2: Neutrophil Activating Peptide-2 (CXCL7)
RANTES: Regulated upon Activation Normal T Expressed and Secreted (CCL5)
SDF-1α: Stromal Cell-Derived Factor 1α (CXCL12)
TARC: Thymus Activation-Regulated Chemokine (CCL17)
TECK/CKβ 15: Thymus-expressed chemokine (CCL25)
vMIP-II: Viral macrophage inflammatory protein II

h: human
m: mouse
r: rat