Chemokine receptor

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Chemokine receptors are G-protein-linked 7-transmembrane receptors expressed on the surfaces of certain cells.

They interact with small extracellular protein ligands known as chemokines. Following interaction with their specific ligands, chemokine receptors trigger a flux in intracellular calcium (Ca²⁺) ions (calcium signaling), which generates a chemotactic response of that cell, thus trafficking the cell to a desired location within the organism. These chemokine receptors are divided into different families according to which family of chemokines they bind (CC, CXC, C, or CX3C).

Typical structure of a chemokine receptor, with seven transmembrane domains and a characteristic "DRY" motif in the second intracellular domain. Chemokine receptors are usually linked to a G-protein through which they signal.

[edit] CXC Chemokine Receptors

There are currently seven known CXC receptors in mammals:

[edit] CXCR1 and CXCR2

CXCR1 and CXCR2 are closely related receptors that recognize CXCL8 (otherwise known as interleukin-8) and other ELR-positive chemokines. They are both expressed on the surface of neutrophils in mammals.

[edit] CXCR3

This receptor is predominantly expressed on T lymphocytes, and also on other lymphocytes (some B cells and NK cells) and is highly induced following cell activation. It has three highly related ligands in mammals, CXCL9, CXCL10 and CXCL11.

[edit] CXCR4

CXCR4 (also known as fusin) is the receptor for a chemokine known as CXCL12 (or SDF-1) and, as with CCR5, is utilized by HIV-1 to gain entry into target cells. This receptor has a wide cellular distribution, with expression on most immature and mature hematopoietic cell types (e.g neutrophils, monocytes, T and B cells, dendritic cells, Langerhans cells and macrophages. In addition, CXCR4 can also be found on vascular endothelial cells and neuronal/nerve cells.

[edit] CXCR5

This chemokine receptor is selectively expressed on B cells and is involved in lymphocyte homing and the development of normal lymphoid tissue. Its principle ligand is CXCL13 (or BLC).

[edit] CXCR6

Was formerly called three different names (STRL33, BONZO, and TYMSTR) before being assigned CXCR6 based on its chromosomal location (within the chemokine receptor cluster on human chromosome 3p21) and its similarity to other chemokine receptors in its gene sequence. CXCR6 binds the ligand CXCL16. Curiously, though, CXCR6 is structurally more closely related to CC chemokine receptors than to other CXC chemokine receptors

[edit] CXCR7

CXCR7 was originally called RDC-1 (an orphan receptor) but has since been shown to cause chemotaxis in T lymphocytes in response to CXCL12 (the ligand for CXCR4) prompting the renaming of this molecule as CXCR7. There is no information publically available to confirm whether this designation has been accepted by the IUIS/WHO Subcommittee on Chemokine Nomenclature at this time. This receptor has also been identified on memory B cells.

[edit] CC Chemokine Receptors

To date, ten true members of the CC chemokine receptor family have been described. These are named CCR1 to CCR10 according to the IUIS/WHO Subcommittee on Chemokine Nomenclature.

[edit] CCR1

CCR1 was the first CC chemokine receptor identified and binds multiple inflammatory/inducible (see inducible gene) CC chemokines (including CCL4, CCL5, CCL6, CCL14, CCL15 and CCL16). In humans, this receptor can be found on peripheral blood lymphocytes and monocytes. There is some suggestion that this chemokine receptor is restricted to memory T-cells within the lymphocyte pool. This receptor is also designated cluster of differentiation marker CD191.

[edit] CCR2

CCR2 can interact with CCL2, CCL8 and CCL16 and has been identified on the surface of monocytes, activated memory T cells, B cells, and basophils in humans, and also in peritoneal macrophages in mice. CCR2 is also designated CD192.

[edit] CCR3

CCR3 is a receptor for multiple inflammatory/inducible CC chemokines (including CCL11, CCL26, CCL7, CCL13 and CCL5) that attract eosinophils. It is most highly expressed in both eosinophils and basophils, but can also be found in Th1 and Th2 cells and airway epithelial cells. Thus CCR3 plays a role in allergic reactions. CCR3 is also known as CD193.

[edit] CCR4

CCR4 is expressed on Th2 T lymphocytes and is up-regulated by T cell receptor activation. However, some reports suggest a role for this receptor also in trafficking of dendritic cells. The CC chemokines CCL3, CCL5, CCL17 and CCL22 signal through this receptor.

[edit] CCR5

CCR5 is expressed on several cell types including peripheral blood-derived dendritic cells, CD34+ hematopoietic progenitor cells and certain activated/memory Th1 lymphocytes. This receptor is well defined as a major coreceptor implicated in susceptibility to HIV-1 infection and disease. This receptor has several CC chemokine ligands including CCL2, CCL3, CCL4, CCL5, CCL11, CCL13, CCL14 and CCL16.

[edit] CCR6

The receptor for CCL20 that is expressed on unactivated memory T-cells and some dendritic cells. CCR6 is down-regulated in activated T-cells.

[edit] CCR7

CCR7 is a highly important receptor with a role in trafficking of B and T lymphocytes and dendritic cells to and across high endothelial venules and positioning those cells correctly in T cell zones of secondary lymphoid organs. Its ligands include the related chemokines CCL19 and CCL21, (previously called ELC and SLC).

[edit] CCR8

This receptor is associated with Th2 lymphocytes and is therefore found predominantly in the thymus (in humans) although some expression can be found in the brain, spleen, lymph node, and monocytes at the nucleotide level. The ligand for this receptor is CCL1.

[edit] CCR9

CCR9 was previously called orphan receptor GPR 9-6 and is very highly expressed in thymus (on both immature and mature T-cells) while low in lymph nodes and spleen. CCR9 is also abundant in the gut, with its expression associated with T cells of the intestine. The specific ligand of this receptor is CCL25. To note, the chemokine binding protein D6 had previously been named CCR9, but this molecule is a scavenger receptor not a true (signaling) chemokine receptor.

[edit] CCR10

Receptor for CCL27 and CCL28 that was originally called orphan receptor GPR2. CCR10 has been implicated in inflammation of the skin, and has been shown to recruit regulatory T cells (Tregs) to mucosal layers.

[edit] CCR11 (or NOT!)

This molecule was originally designated CCR11 due to its ability to bind several CC chemokines (including CCL19, CCL21 and CCL25) and its structural similarity to chemokine receptors. However, due to the inability of this molecule (also known as CCRL1 and CCX CKR) to generate a signal following ligand interaction, it has been suggested that it is a scavenger receptor for chemokines and not a bonafide chemokine receptor. Thus CCRL1 should not be called CCR11 under the guidelines of the IUIS/WHO Subcommittee on Chemokine Nomenclature.

[edit] C chemokine receptors

This sub-family of chemokine receptors contains only XCR1, the receptor for XCL1 and XCL2 (or lymphotactin-1 and -2). XCR1 is also known as GPR5.

[edit] CX₃C chemokine receptors

Only one member belongs to this sub-family of chemokine receptors - CX₃CR1. As the name suggests, this receptor binds the chemokine CX₃CL1 (or Fractalkine). Expression of this receptor appears to be associated with lymphocytes.

[edit] further reading

• Murphy, International Union of Pharmacology. XXX. Update on chemokine receptor nomenclature, Pharmacological Reviews, 2002, 54:227-229.

• Murphy et al., International union of pharmacology. XXII. Nomenclature for chemokine receptors, Pharmacological Reviews, 2002, 52:145-76.

• Balabanian et al., The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes,JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280:35760-35766.

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[edit] External links

• IUPHAR RECEPTOR DATABASE
• The Cytokine Receptor Database