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 Gai proteins, although there is considerable evidence for additional Gaq 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 (Kd <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 Gi (PI hydrolysis, PI3K)
(cAMP modulation)
Gi (PI hydrolysis, PI3K)
(cAMP modulation)
Gi (PI hydrolysis, PI3K)
(cAMP modulation)
Gi (PI hydrolysis, PI3K)
(cAMP modulation)
Gi (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 Gi (PI hydrolysis, PI3K)
(cAMP modulation)
Gi (PI hydrolysis, PI3K)
(cAMP modulation)
Gi (PI hydrolysis, PI3K)
(cAMP modulation)
Gi (PI hydrolysis, PI3K)
(cAMP modulation)  
Gi (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 Gi (PI hydrolysis, PI3K)
(cAMP modulation)
Gi (cAMP modulation)
(PI hydrolysis, PI3K)
Gi (PI hydrolysis, PI3K) Gi (PI hydrolysis, PI3K) Gi (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 Gi (PI hydrolysis, PI3K) Gi (PI hydrolysis, PI3K) Gi (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
Gi (cAMP modulation)
Gq/11 (increase IP3/DAG)
Gi (cAMP modulation)
Gq/11 (increase IP3/DAG)
Gi (cAMP modulation) (PI hydrolysis) Gi (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

 

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References