| Chemokine receptor family | |
|---|---|
 Typical structure of achemokine receptor, with seven transmembrane helices and a characteristic "DRY" motif | |
| Identifiers | |
| Symbol | Chemokine_rcpt |
| InterPro | IPR000355 |
Chemokine receptors arecytokine receptors found on the surface of certain cells that interact with a type ofcytokine called achemokine.[1][2] There have been 20 distinct chemokine receptors discovered in humans.[3] Each has arhodopsin-like 7-transmembrane (7TM) structure and couples toG-protein forsignal transduction within a cell, making them members of a large protein family ofG protein-coupled receptors. Following interaction with their specific chemokineligands, chemokine receptors trigger aflux inintracellular calcium (Ca2+) ions (calcium signaling). This causes cell responses, including the onset of a process known aschemotaxis that traffics the cell to a desired location within the organism. Chemokine receptors are divided into different families,CXC chemokine receptors,CC chemokine receptors,CX3C chemokine receptors andXC chemokine receptors that correspond to the 4 distinct subfamilies of chemokines they bind. The four subfamilies of chemokines differ in the spacing of structurally important cysteine residues near the N-terminal of the chemokine.[4]
Chemokine receptors areG protein-coupled receptors containing 7transmembrane helices[5] that are found predominantly on the surface ofleukocytes. Approximately 19 different chemokine receptors have been characterized to date, which share many common structural features. They are composed of about 350amino acids that are divided into a short and acidic N-terminal end, seven transmembrane helices with threeintracellular and threeextracellularhydrophilic loops, and an intracellular C-terminus containingserine andthreonine residues that act asphosphorylation sites during receptor regulation. The first two extracellular loops of chemokine receptors are linked together bydisulfide bonding between two conservedcysteine residues. TheN-terminal end of a chemokine receptor binds to chemokines and is important for ligand specificity.G-proteins couple to the C-terminal end, which is important for receptor signaling following ligand binding. Although chemokine receptors share high amino acid identity in their primary sequences, they typically bind a limited number of ligands.[6] Chemokine receptors are redundant in their function as more than one chemokine is able to bind to a single receptor.[4]
Intracellular signaling by chemokine receptors is dependent on neighbouring G-proteins. G-proteins exist as a heterotrimer; they are composed of three distinct subunits. When the moleculeGDP is bound to the G-protein subunit, the G-protein is in an inactive state. Following binding of the chemokine ligand, chemokine receptors associate with G-proteins, allowing the exchange of GDP for another molecule calledGTP, and the dissociation of the different G protein subunits. The subunit called Gα activates anenzyme known asPhospholipase C (PLC) that is associated with thecell membrane. PLC cleavesPhosphatidylinositol (4,5)-bisphosphate (PIP2) to form twosecond messenger molecules calledinositol triphosphate (IP3) anddiacylglycerol (DAG); DAG activates another enzyme calledprotein kinase C (PKC), and IP3 triggers the release ofcalcium from intracellular stores. These events promote many signaling cascades, effecting a cellular response.[7]
For example, when CXCL8 (IL-8) binds to its specific receptors,CXCR1 orCXCR2, a rise in intracellular calcium activates the enzymephospholipase D (PLD) that goes on to initiate an intracellular signaling cascade called theMAP kinase pathway. At the same time, the G-protein subunit Gα directly activates an enzyme calledprotein tyrosine kinase (PTK), which phosphorylatesserine andthreonine residues in the tail of the chemokine receptor, causing its desensitisation or inactivation.[7] The initiatedMAP kinase pathway activates specific cellular mechanisms involved inchemotaxis,degranulation, release ofsuperoxide anions, and changes in the avidity ofcell adhesion molecules calledintegrins.[6] Chemokines and their receptors play a crucial role in cancer metastasis as they are involved in extravasation, migration,micrometastasis, and angiogenesis.[4] This role of chemokine is strikingly similar to their normal function of localizing leukocytes to an inflammatory site.[4]
Fifty chemokines have been discovered so far, and most bind onto CXC and CC families.[4] Two types of chemokines that bind to these receptors are inflammatory chemokines and homeostatic chemokines. Inflammatory chemokines are expressed upon leukocyte activation, whereas homeostatic chemokines show continual expression.[3]