Chemokines are chemoatractant cytokines that activate cellular responses like controlling migration of leukocytes, coordinating the traffic during immune and inflammatory response, they are induced by cytokines, growth factors and pathogens(Murphy, Baggiolini et al. 2000). In addition to that, chemokines act on different cell (e.g. hematopoietic progenitor cells, fibroblasts, dendritic cells, keratinocytes), play role in angiogenesis, wound healing and in viral infections(Niederlova and Koubek 1999). More than 50 chemokines have been discovered and at least 18 human chemokine receptors(Chen, Oppenheim et al. 2004). They have been grouped into four groups according to the cysteine residue in their polypeptide near N-terminal of the receptor either having one cysteine (C chemokines), two adjacent cysteine (C-C chemokines), cysteine separated by one (C-X-C chemokines) or separated by three residues (C-XXX-C chemokines)(Rang, Ritter et al. 2014).
Chemokines signal through cell surface G protein-coupled superfamily of seven-transmembrane receptors (7TM). There are two types of receptors that bind to chemokines; typical (conventional chemokine receptors (cCKRs) and atypical chemokine receptors (ACKRs)(Hughes and Nibbs 2018).
There are the general features of GPCRs which represent a 7 transmembrane domains with three intracellular and three extracellular hydrophobic loops.
However, there are many features that are found frequently among chemokine receptors than other GPCRs which include: composed of about 340 to 370 amino acid, acidic extracellular N-terminal end that may be sulfated of tyrosine residue and contain N-linked glycosylation sites, an intracellular C-terminus that contains serine and threonine residues which act as phosphorylation sites for receptor regulation, DRYLAIVHA sequence (conserved sequence) or a variation of it is found in the second intracellular loop, a short basic third intracellular loop, in most cases there is a cysteine residue at each of the four extracellular domains and a tyrosine sulfation motif is commonly found near the N terminus of receptors (important for posttranslational modification for protein-protein interaction also has been shown to be critical for HIV coreceptor activity for CCR(Farzan, Mirzabekov et al. 1999; Murdoch and Finn 2000).
The 3D structure of chemokine receptors is not yet known, but a reasonable working model can be illustrated for the transmembrane domains based on analogy with rhodopsin.
Below figure shows a diagrammatic representation of CXCR1 which provides a good example for the general chemokine receptor structure where Extracellular N-terminal acidic residues are shaded, C-terminal potential phosphorylation residues (serine and threonine) are black, and conserved cysteines are hatched.
When the molecule GDP is bound to G-protein it is inactive, then upon ligand binding, it changes to GTP which activates the receptor due to dissociation of the different G protein subunits into G? and G? subunits. The G? activates a membrane associated enzyme known as phospholipase C?2 (PLC) which in turn cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) to form two intracellular second messengers molecules; phosphatidylinositol 1,4,5-triphosphate (IP3) and diacyl-glycerol (DAG).
IP3 triggers the mobilization of calcium from intracellular stores, whereas DAG acts in conjunction with calcium to activate various isoforms of protein kinase C (PKC). Rapid increase in intracellular calcium activates PLD. Meanwhile G?i2directly activates PTK. This collectively activate MAP kinases and phosphorylate the serine and threonine residues located on the C-termini of CXCR1, leading to receptor inactivation. MAP kinases activate phospholipase A2.
DAG, intracellular calcium, PKC, and phospholipase A2 (PLA2) all interact with specific cell activation mechanisms, leading to cell motility, degranulation, modification of integrin avidity and release of superoxide anions (Murdoch and Finn 2000).
The following figure shows a model of chemokine receptor activation and signal transduction for IL-8 (the main ligand for CXCR1) and neutrophils.
Regarding CXCR1 as an illustration example, it is expressed in tissues e.g. bone marrow, heart, retina, placenta and lungs. Also in cells e.g. neutrophils, monocytes, mast cells, CD8 T cells, natural killer cells, basophils, fibroblasts, keratinocytes, endothelial cells, neurons and melanocytes(Sapoznik, Kozlovski et al. 2014). Upon binding of the ligand various processes are induced; in neutrophils, receptor activation induce migration of neutrophils, release of granule enzymes and formation of superoxide in respiratory burst (Holmes, Lee et al. 1991; Jones, Wolf et al. 1996). In addition to the actions on immune cells, CXCR1 also play role in the regulation of vasculogenesis and consequent tumor growth (Strieter, Polverini et al. 1995).
CXCR1 is over-expressed in melanoma, breast cancer, colorectal cancer, prostate cancer, nasopharyngeal carcinoma, chronic obstructive pulmonary disease (COPD), urinary tract infection recurrent and psoriasis(Sapoznik, Kozlovski et al. 2014).
Different aspects of chemokine receptors biology- ligands and signaling transduction- are certain to be followed also the linkage between receptor expression and various disease states specially cancer and HIV is an area for more light to be spotted on.
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