Roleof?-arrestinsinthedesensitization,sequestrationandintracellulartraffickingofGPCRs.HomologousdesensitizationofGPCRs(1)resultsfromthebindingof?-arrestins(?-arr)toagoNIST-occupiedreceptorsfollowingphosphorylationofthereceptorbyGRKs.?-arrestinbindingstericallyprecludescouplingbetweenthereceptorandheterotrimericGproteins,leADIngtoterminationofsignalingbyGproteinseffectors.Receptor-bound?-arrestinsalsoactasadapterproteins,bindingtocomponentsoftheclathrinendocyticmachineryincludingclathrin,?2-adaptin(AP-2).Receptorsequestration(2)reflectsthedynamin(Dyn)-dependentendocytosisofGPCRsviaclathrin-coatedpits.Onceinternalized,GPCRsexhibittwodistinctpatternsof?-arrestininteraction.`ClassA"GPCRs,forexamplethe?2adrenergicreceptor,rapidlydissociatefrom?-arrestinuponinternalization.Thesereceptorsaretraffickedtoanacidifiedendosomalcompartment,whereintheligandisdissociatedandthereceptordephosphorylatedbyaGPCR-specificproteinphosphatasePP2Aisoform,andaresubsequentlyrecycledtotheplasmamembrane(3).`ClassB"receptors,forexampletheangiotensinIIAT1areceptor,formstablereceptor-?-arrestincomplexes.Thesereceptorsaccumulateinendocyticvesiclesandareeithertargetedfordegradationorslowlyrecycledtothemembraneviaasyetpoorlydefinedroutes.

Contributor:KosiGramatikoff,PhD

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