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1、THEJOURNALOFBIOLOGICALCHEMISTRYMinireviewVol.273,No.30,IssueofJuly24,pp.18677±18680,1998©1998byTheAmericanSocietyforBiochemistryandMolecularBiology,Inc.PrintedinU.S.A.phorylationanddesensitizationofanyGPCRcontaininganappro-GProtein-coupledReceptorspriatePKAa
2、nd/orPKCconsensusphosphorylationsite.GRKsandb-ArrestinsÐThemajorcellularmechanismmediat-III.NEWROLESFORRECEPTORKINASESANDingrapid,agonist-specific,orhomologousdesensitizationofGpro-b-ARRESTINSINRECEPTORSIGNALINGANDtein-coupledreceptorsconsistsofatwo-stepproc
3、essinwhichtheDESENSITIZATION*agonist-occupiedreceptorsarephosphorylatedbyaGRKandthenbindanarrestinprotein,whichstericallyinterdictssignalingtotheRobertJ.Lefkowitz³Gprotein.Thesemechanismshavebeenextensivelyreviewedelse-where(1,2,7±10).ThefamilyofGRKscurrentl
4、yincludessixFromtheDepartmentsofMedicine(Cardiology)members(GRKs1±6),ofwhichthemostthoroughlyinvestigatedandBiochemistry,HowardHughesMedicalInstitute,arerhodopsinkinase(GRK1)andbARK1(GRK2).DukeUniversityMedicalCenter,Thearrestinfamilyincludesatleastsixmember
5、s,severalofDurham,NorthCarolina27710whichundergoalternativesplicing(2,10).Someformsarefoundinthebrainandmanyothertissues(e.g.b-arrestins1and2),whereas1OfthemanyformsofGPCRregulationnonehasreceivedasothersareconfinedtotheretina(e.g.visualarrestins,conearres-m
6、uchattentionastheprocessofreceptordesensitization,i.e.thetin).DirectbindingstudieshavedemonstratedthatGRK-catalyzedwaningresponsivenessofthereceptorsinthefaceofpersistentphosphorylationofb-adrenergicreceptorsincreasesaffinityof2stimulation(1,2).Numerousmecha
7、nismshavebeendiscovered,b-arrestinbinding10±30-foldwhereasagonistoccupancyoftheincludingthosethatoperateatthetranscriptional,translational,receptorshasamuchlesssignificanteffectontheaffinityofthisandproteinlevels.Thelattercategoryinturnincludesmecha-Download
8、edfrominteraction(11,12).Theregionsonthearrestinsthatbindtothenismsthatregulatetherateofdegradationofthereceptors.Fi-intracellularloopsofthereceptorshavebeenmapped(13).nally,therearemechanismsfo
