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Homologous desensitization of GPCRs results from the binding of b-arrestins (b-arr) to agonist -occupied receptors following phosphorylation of the receptor by GRKs. b-arrestin binding sterically precludes coupling between the receptor and heterotrimeric G proteins, leading to termination of signaling by G proteins effectors. Receptor-bound b-arrestins also act as adapter proteins, binding to components of the clathrin endocytic machinery including clathrin, b2-adaptin (AP-2). Receptor sequestration reflects the dynamin (Dyn)-dependent endocytosis of GPCRs via clathrin-coated pits. Once internalized, GPCRs exhibit two distinct patterns of b-arrestin interaction. Class A GPCRs, for example the b2 adrenergic receptor, rapidly dissociate from b-arrestin upon internalization. These receptors are trafficked to an acidified endosomal compartment, wherein the ligand is dissociated and the receptor dephosphorylated by a GPCR-specific protein phosphatase PP2A isoform, and are subsequently recycled to the plasma membrane. Class B receptors, for example the angiotensin II AT1a receptor, form stable receptor-b-arrestin complexes. These receptors accumulate in endocytic vesicles and are either targeted for degradation or slowly recycled to the membrane via as yet poorly defined routes. (This definition may be outdated - see the DesignNote.)
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