??Arrestin1 and GPCR kinase2 play permissive roles in Src?mediated endocytosis of ?4?2 nicotinic ACh receptors

Background and Purpose The ?4?2 nicotinic ACh receptor (nAChR), a subtype of the ligand-gated ion channel, is abundantly expressed in brain implicated several neurological disorders. endocytosis nAChRs plays important roles pathogenesis diseases, but underlying molecular mechanisms remain poorly understood. Experimental Approach Loss-of-function approaches mutants that display different endocytic properties were used to identify cellular components processes responsible for endocytosis. signalling cascade leads was deduced via protein interactions predicted components. determined crosschecked using an ELISA radioligand assay. Key Results Endocytosis occurred through clathrin-mediated dynamin-dependent manner. 14-3-3?-dependent Src-mediated phosphorylation nAChR ?4 subunit at Y575 required endocytosis, this with assistance ?-arrestin1 GPCR kinase 2 (GRK2) without need activity. triggered mouse double minute homologue-mediated ubiquitination subsequent down-regulation nAChRs. Conclusions Implications nAChR, ionophore receptor, employs metabotropic pathway which down-regulation. Further, GRK2 ?-arrestin1, usually associated signalling, are involved mechanisms. Considering functional pathological implications results obtained study crucial progression basic research clinical investigations.