Chemokine GPCR Family Subtypes and Products

What Are Chemokine Receptors?

Chemokine receptors are a very large family of G protein-coupled receptors (GPCRs) that binds the cytokine, chemokine. Chemokine receptors can be broken down into four main subtypes: CXC chemokine receptors, CC chemokine receptors, CX3C chemokine receptors, and XC chemokine receptors, named after the families of chemokines they bind to. Chemokines are a family of proteins responsible for trafficking leukocyte under inflammatory and homeostatic conditions. Certain chemokines also play a role in inhibiting or promoting tumor activity, inhibiting HIV activity, gene expression modulation, and antimicrobial activity. Progress has been made in identifying chemokine receptor antagonists for the treatment of immunologically mediated inflammatory diseases, such as atherosclerosis, glomerulonephritis, and cardiac graft rejection. A few are currently undergoing clinical trials.

Chemokine Receptor Information

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CCR1 is a CC chemokine receptor with high affinity for RANTES. It is demonstrated that targeted disruption of the CCR1 receptor is associated with protection from pulmonary inflammation secondary to acute pancreatitis in the mouse. The protection from lung injury is associated with decreased levels of TNF- alpha in a temporal sequence indicating that the activation of the CCR1 receptor is an early event in the systemic inflammatory response syndrome.

CCR2 (C-C chemokine receptor type 2 or monocyte chemoattractant protein 1 receptor) is a receptor for the MCP-1, MCP-3 and MCP-4 chemokines. It is also an alternative coreceptor with CD4 for HIV-1 infection. CCR2 has been widely considered as a potential therapeutic target for autoimmune disease and inflammatory disorders of the lung, particularly rheumatoid arthritis, and various CCR2 blocking agents have been developed, some of which might have therapeutic values.

CCR3 (C-C chemokine receptor type 3 or eosinophil eotaxin receptor) is a receptor for a C-C type chemokine and binds to eotaxin, eotaxin-3, MCP-3, MCP- 4, RANTES and MIP-1 delta. The receptor subsequently transduces a signal by increasing the intracellular calcium level. Similar to CCR2, it is another alternative coreceptor with CD4 for HIV-1 infection. CCR3 is expressed on eosinophils, basophils, mast cell subpopulations, activated Th2 cells, macrophages and airway epithelial cells. Hence, CCR3 is closely associated with asthma and allergy and blockade of this receptor may have pronounced beneficial effects in these diseases.

CCR4 (C-C chemokine receptor type 4) is a high affinity receptor for the C-C type chemokines CCL17/TARC and CCL22/MDC. CCR4 receptors express in the thymus, peripheral blood leukocytes and the spleen. CCR4 functions as a chemoattractant homing receptor on circulating memory lymphocytes and as a coreceptor for some primary HIV-2 isolates. In the CNS, CCR4 mediates hippocampal-neuron survival. CCR4 is one of the type 2 T helper cell (Th2) markers. Th2 cells are recruited to the asthmatic lung in response to allergen challenge and CCR4 has been therefore considered as a therapeutic target of lung inflammation, including eosinophilic inflammation of the lung and asthma. In addition, CCR4 has been reported as a potential independent and significant prognostic factor for adult T- cell leukemia/lymphoma (ATLL).

CCR5 (chemokine (C-C motif) receptor 5) is a receptor for C-C type chemokines MIP-1-α, MIP-1-ß and CCL5. CCR5 plays a role in the control of granulocytic lineage proliferation or differentiation. It also acts as co-receptor with CD4 for primary non-syncytium-inducing strains (macrophage-tropic) of HIV-1 virus.

CCR6 is a receptor for macrophage inflammatory protein (MIP)-3α (CCL20). It is expressed in immature dendritic cells as well as in B lymphocytes and memory T cells. In gene-targeted mice lacking CCR6, myeloid dendritic cells are either absent or underrepresented in the subepithelial dome compared with wild-type mice. CCR6 and its ligands contribute to the normal homeostatic regulation of extrathymic T cell development in the intestine.

CCR7 (C-C chemokine receptor type 7 is a receptor for the chemokine MIP-3β. CCR7 has been identified as a key regulator of homeostatic B and T cell trafficking to secondary lymphoid organs. CCR7 is also an essential mediator for entry of both dermal and epidermal dendritic cells into the lymphatic vessels within the dermis. CCR7 plays an important role in tumor cell migration and lymph node metastasis. Expression of CCR7 is related to the development of lymph node metastasis in nonsmall cell lung cancers.

CCR8 (C-C chemokine receptor type 8) is a receptor for the chemokines CCL1 (I-309). The receptor regulates monocyte chemotaxis and thymic cell line apoptosis, and is an additional alternative coreceptor with CD4 for HIV-1 infection. CCR8 plays a role on cell types of relevance to respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD) and chronic bronchitis. The interference of CCR8 from its ligand represents a new approach in allergy therapy.

CCR9 (C-C chemokine receptor type 9) is a thymus-specific receptor for chemokine CCL25 (SCYA25 or TECK). It is an alternative co-receptor with CD4 for HIV-1 infection. Activation of the receptor may lead to potent cFLIP(L)- independent resistance to cycloheximide-induced apoptosis and modest resistance to Fas-mediated apoptosis possibly via activation of multiple signaling components involving Akt and glycogen synthase kinase 3β. Thus, dissection of signaling components involved in the CCR9-mediated antiapoptosis could be a framework for cell survival mechanisms and may provide options for therapeutic interventions.

CCR10 (also known as GPR2) is selectively expressed by IgA- secreting cells including circulating IgA+ plasmablasts, as well as almost all IgA+ plasma cells in the salivary gland, small intestine, large intestine, appendix and tonsils. It is a receptor for CCL27/CTACK and CCL28/MEC. Expression of CCL27 in skin may play an important role in facilitating memory T cells that express CCR10 to enter into cutaneous sites during inflammation and in determining the metastatic destination of malignant melanoma.

Chemokine receptor-like 1 (CMKLR1) (or ChemR23) is a receptor for TIG2 and Chemerin. ChemR23/Chemerin may play a key role in directing plasmacytoid dendritic cells trafficking. The receptor also acts as a coreceptor for several SIV strains (SIVMAC316, SIVMAC239, SIVMACL7E-FR and SIVSM62A), as well as a primary HIV-1 strain (92UG024-2).

CX3CR1, (CX3C-chemokine receptor 1, fractalkine receptor or GPR13) is a receptor for the CX3C chemokine fractalkine. CX3CR1 is expressed in cytotoxic effector lymphocytes, including natural killer cells, cytotoxic T lymphocytes and macrophages. Soluble fractalkine causes migration of these cells, whereas the membrane-bound form captures and enhances the subsequent migration in response to secondary stimulation with other chemokines. Furthermore, stimulation through membrane-bound fractalkine activates natural killer cells, leading to increased cytotoxicity and interferon-gamma production. Fractalkine is involved in the pathogenesis of various clinical disease states or processes, such as atherosclerosis, glomerulonephritis, cardiac allograft rejection and rheumatoid arthritis. In addition, polymorphisms in CX3CR1, which reduce its binding activity to fractalkine, have been reported to increase the risk of HIV disease and to reduce the risk of coronary artery disease.

CXCR1 is a high affinity interleukin-8 receptor (IL-8RA). Binding of IL-8 to the receptor causes activation of neutrophils. Neutrophils have been implicated in the pathogenesis of many inflammatory lung diseases, including acute respiratory distress syndrome, chronic obstructive pulmonary disease, and asthma. Antagonists of CXCR1 may block in vivo trafficking of neutrophils, suggesting that antagonism of IL-8 at the receptor level is a viable therapeutic strategy.

CXCR2 (high affinity interleukin-8 receptor B, IL8RB) is a receptor to interleukin-8, which is a powerful neutrophil chemotactic factor. Binding of IL-8 to the receptor causes activation of neutrophils. This receptor also binds to GRO/MGSA and NAP-2 with high affinity. Some highly potent small molecule antagonists of CXCR2 showed success in blocking in vivo trafficking of neutrophils, suggesting that antagonism of IL-8 at the receptor level is a viable therapeutic strategy in conditions such as pulmonary disease.

CXCR3 (chemokine receptor 3) is a receptor for SCYB9/MIG, SCYB10/INP10 and SCYB11/ITAC. The chemokines that target CXCR3 in concert with Th1 cytokine appear to play a beneficial role to atopic disorders including a range of conditions such as allergic asthma, -rhinitis, -conjunctivitis, -dermatitis, food and drug allergies and anaphylaxis.

CXCR4 is a receptor for the C-X-C chemokine SDF-1 (Stromal Cell-Derived Factor 1). It is involved in haematopoiesis and cardiac ventricular septum formation, and plays an essential role in vascularization of the gastrointestinal tract, cerebellar development and survival of hippocampal-neuron of central nerve system. CXCR4 also acts as a primary receptor for some HIV-2 isolates and as a co-receptor with CD4 for HIV-1 X4 viruses.

CXCR5 (CXC-chemokine receptor 5, or Burkitt lymphoma receptor 1) is a receptor for CXCL13 and expresses in mature B-cells, a subpopulation of T-cells and Burkitt lymphoma cells. CXCR5 exerts possibly a regulatory function in Burkitt lymphoma lymphomagenesis and/or B-cell differentiation. It is a potential candidate for cell-cell interaction and activation of mature B-lymphocytes in lymphatic tissues.

CXCR6 (CXC-chemokine receptor type 6) is a receptor for CXC chemokine CXCL16. CXCR6 is expressed by naive CD8 T cells, natural killer T cells, a subset of memory CD4 T cells and plasma cells. CXCR6 and its ligand play an important role in the trafficking of the cells expressing them. It is demonstrated that CXCL16+ macrophages in synovial fluid of rheumatoid arthritis patients lead to recruitment of CXCR6+ memory T cells, thereby contributing to the inflammatory cascade associated with rheumatoid arthritis pathology. CXCR6 is also used as a coreceptor by simian immunodeficiency viruses (SIVs) and by strains of HIV-2 and M-tropic HIV-1.

CXCR7 (or RDC1) is a recently deorphanized G-protein coupled receptor which binds with high affinity the inflammatory and homing chemokines CXCL11/ITAC and CXCL12/SDF-1. CXCR7 is expressed in bladder, spleen, heart, skeletal muscle, peripheral nervous system and placenta. CXCR7 does not mediate typical chemokine receptor responses such as leukocyte trafficking. Recent findings in zebrafish indicate that a critical activity of the receptor is scavenging of CXCL12 thereby generating guidance cues for CXCR4-dependent migration.

Chemokines and their receptors play a vital role in the regulation of responses in the immune system and in the recruitment of certain lymphocytes. The human chemokine receptor XCR1 is a G-protein-coupled receptor with 333 amino acids. Specifically, XCR1 has been associated with the induction of chemotaxis and has been identified in neutrophils, t-lymphocytes, b-lymphocytes through RT-PCR.

Receptor FamilyReceptorSpeciesParentalStable Cell Lines Division-Arrested Cells Membranes
CCR1humanHEK293T Gαqi5CG1009DCG1009MCG1009
CCR3human HEK293T Gαqi5CG1011DCG1011MCG1011
CCR4humanHEK293T Gαqi5CG1012DCG1012MCG1012
CCR5humanHEK293T Gαqi5CG1013DCG1013MCG1013
CCR7humanHEK293T Gαqi5CG1015DCG1015MCG1015
CCR8humanHEK293T Gαqi5CG1016DCG1016MCG1016
CCR9dogHEK293T Gαqi5CGd1017DCGd1017MCGd1017
CCR9humanHEK293T Gαqi5CG1017DCG1017MCG1017
CCR9humanHEK293T Gαqi5CG1017ADCG1017AMCG1017A
CCR9mouseHEK293T Gαqi5CGm1017DCGm1017MCGm1017
CCR9ratHEK293T Gαqi5CGr1017DCGr1017MCGr1017
CCR10humanCHO-K1 Gαqi5CG1018-1DCG1018-1MCG1018-1
CMKLR1humanHEK293T Gαqi5CG1147DCG1147MCG1147
CX3CR1humanHEK293T Gαqi5CG1008aDCG1008aMCG1008a
CX3CR1humanHEK293T Gαqi5CG1008bDCG1008bMCG1008b
CXCR1humanHEK293T Gαqi5CG1001DCG1001MCG1001
CXCR2humanHEK293T Gαqi5CG1002DCG1002MCG1002
CXCR3humanHEK293T Gαqi5CG1003DCG1003MCG1003
CXCR4humanHEK293T Gαqi5CG1004DCG1004MCG1004
CXCR6humanHEK293T Gαqi5CG1006DCG1006MCG1006
XCR1humanHEK293T Gαqi5CG1007DCG1007MCG1007