Syntaxin-1a和granuphilin在胰岛素释放中的作用(4)

37

uledockingisimpairedinchromaffincellsexpressingbotuli-numneurotoxinCandthusissyntaxin-dependent(27).However,itshouldbenotedthatthisneurotoxincleavessyntaxin-1–3aswellasSNAP-25(28).BecauseadockingdefecthasalsobeenreportedinSNAP-25nullchromaffincellsbythesamegroup(24),ithasnotbeenadequatelydeterminedwhetheranysyntaxinsareinvolvedingranuledocking.BesidesSNAP-25,thisfindingsimplyindicatesthatallsyntaxins,includingsyntaxin-1–3,canparticipateinthedockingofchro-maffingranules,assuggestedforinsulingranulesbasedonthesefindings.Alternatively,theminordockingdefectinthesyntaxin-1anull cellsmayindirectlyresultfromthedecreasedexpressionlevelofgranuphilin.Itisalsopossiblethatgranuphilinmediatesgranuledockingthroughthephospho-lipidbindingactivityofitsC2domains,asfoundinanotherRab27effector,exophilin4,inpancreatic cells(29).Inthosecases,nosyntaxinwouldbeinvolvedinthedockingprocess.Itisinterestingthatneithersyntaxin-4noritspartner,Munc18-3(23),interactswithgranuphilin,althoughpancreatic cellsofmiceheterozygousforthesyntaxin-4mutation(19),orfortheMunc18-3mutation(30),doshowsignificantdecreasesininsulinsecretion.Thesefindingssuggestthatthosemoleculesarenotinvolvedingranuledockingorpossiblyinthefusionofstablydockedgranules.Consistentwiththishypothesis,Munc18-3depletionselectivelyimpairsthesus-tainedphaseofglucose-inducedinsulinrelease(31),inwhichmostofthefusionisderivedfromundockedgranules(2,3,32).Bycontrast,syntaxin-1a,2,and3maybeinvolvedinthefusionofgranuphilin-mediateddockedgranules.Con-sistently,granuphilin/syntaxin-1adoubleknock-outmiceshowenhancedglucose-inducedinsulinsecretiondespitethelackofsyntaxin-1a,whichsuggeststhatsyntaxin-1aisnotactivelyinvolvedinthefusionofundockedgranulesintheabsenceofgranuphilin.However,itshouldberememberedthatsuchdifferentialrolesofsyntaxinsintheexocytosisofdockedandundockedgranulesdonotnecessarilyaccountfortheirdifferentialrolesinthetimecourseofsecretion.Infact,theheterozygousmutationofsyntaxin-4hasbeenreportedtoselectivelyaffectinsulinsecretioninarelativelyearlyperiod(withinthefirst7min)afterglucosestimulation(19).Further-more,syntaxin-1adeficiencyaffectsinsulinsecretionthrough-outa15-mindepolarizationstimulationintheabsenceofdockedgranulesindoublemutantcells.Therefore,althoughdockedandundockedgranulesmayutilizedifferentsetsoffusionmachinery,theydonotfusesequentially,butratherinparallel,afterstimulation,assuggestedandobservedpreviously(3,4),andanysyntaxincanmediatethefusionofundockedgranulesineitheranearlyorlatephaseofstimulus-inducedsecretion.Futurestudiesshouldexplorethedifferencesbetweenthemoleculardeterminantsoftherate-limitingexo-cyticstepsfordockedandundockedgranules.

Acknowledgments—higomefortheircol-onymanagementofmiceandJ.Toshimaforassistanceinpreparingthe

manuscript.

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RolesofGranuphilinandSyntaxinsinGranuleDocking

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