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Chemokine Receptor Intracellular Signaling

Chemokines are critical regulators of cell migration and chemotaxis, survival, and proliferation. They bind and activate cell surface-localized chemokine receptors. Chemokine receptors are members of the seven-transmembrane G protein-coupled receptor (GPCR) superfamily that initiates intracellular signaling primarily via the activation of heterotrimeric G proteins (Galpha, Gbeta, and Ggamma). GPCRs, including chemokine receptors, are promiscuous and can signal through multiple subtypes of alpha G proteins. Chemokine receptors often activate inhibitory alpha G proteins, leading to the downregulation of Adenylyl Cyclase and a decrease in Cyclic Adenosine Monophosphate (cAMP). Altered cAMP levels modulate Src kinase and CREB transcriptional activity. Chemokine receptor signaling through beta/gamma G protein subunits activates multiple signaling cascades downstream of Phosphatidylinositide 3-kinase (PI-3 K) and Phospholipase C (PLC). Some chemokine receptors also initiate Jak-Stat signaling. Activation of beta/gamma G protein subunits also results in G protein receptor kinase (GRK)-regulated chemokine receptor phosphorylation and the recruitment of beta-Arrestin. beta-Arrestin recruitment to chemokine receptors is associated with Clathrin-mediated receptor internalization and desensitization.