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?arrestins in GPCR Desensitization
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
REFERENCES:AndrewJ.MorrisandCraigC.Malbon.PhysiologicalRegulationofGProtein-LinkedSignalingPhysiolRev,Oct1999;79:1373-1430.K.Palczewski.StructureandfunctionsofarrestinsProteinSci.,Sep1994;3:1355-1361.KLPierceandRJLefkowitz.Classicalandnewrolesofbeta-arrestinsintheregulationofG-protein-coupledreceptors.NatRevNeurosci,Oct2001;2(10):727-33.MoritzBünemannandM.MarleneHosey.G-proteincoupledreceptorkinasesasmodulatorsofG-proteinsignalingJ.Physiol.,May1999;517:5-23.RobertJ.Lefkowitz.GProtein-coupledReceptors.III.Newrolesforreceptorkinasesand-arrestinsinreceptorsignalinganddesensitization.J.Biol.Chem.,Jul1998;273:18677-18680.
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