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1、StructureandMechanismofActionofAMPAandKainateReceptorsMarkL.MayerPorterNeuroscienceResearchCenter,LaboratoryofCellular&MolecularNeurophysiology,NICHD,NIH,Bethesda,MD20892,USA,mayerm@mail.NIH.gov1IntroductionStructuralstudiesonglutamatereceptorionchannels(iGluRs)
2、havereachedalevelofsophisticationthatwasimpossibletoimaginewhentheindividualreceptorgeneswereclonedinthe1980s.Becausethesemembraneproteinsmediateexcitatoryresponsesatapproximately60%ofsynapsesinthebrain,theyhaveattractedenormousinterestduetotheirroleinsynapticpl
3、asticity,learningandmemory,developmentoftheCNS,anddisease.Therehasalsobeenimmenseinterestinunderstandinghowthesemoleculeswork.InthischapterIwillhighlightsomeofthekeyadvancesinourunderstandingofthefunctionofglutamatereceptorionchannelswhichhavearisenfromstructura
4、lwork,andaddresssomeofthemostimportantissueswhichremainunanswered.TheresultsdiscussedfocusalmostentirelyonAMPAandkainatereceptors,whileNMDAreceptorsarediscussedinthechapterbyYuanetal.2MolecularArchitectureOurinitialideasaboutthestructureofiGluRswerestronglyinflu
5、encedbypriorworkonnicotinicacetylcholinereceptorsandrelatedmembersofthecysloopfamilyofligandgatedionchannels.Theseassembleaspentamers,withabarrelstavearchitectureinwhichtheionchannelliesatthecenterofa5-foldaxisofsymmetry(37).FiveyearsafterthefirstiGluRwascloned(
6、14)aseriesofexperimentsusingprincipallybiochemicalandbioinformanticapproachesrevealedthatiGluRshaveastrikinglydifferentarchitecture.Biochemicalexperimentsusingglycosidasesensitivity,andchimericconstructstoidentifytheextracellularligandbindingdomain,unequivocally
7、establishedthecorrectmembranetopologyofiGluRs(13,J.W.Hell,M.D.Ehlers(eds.),StructuralandFunctionalOrganizationoftheSynapse,DOI:10.1007/978-0-387-77232-5_9,©SpringerScience+BusinessMedia,LLC2008252MarkL.Mayer40)andintroducedthenowwidelyusedS1S2nomenclatureforlabe
8、lingthepreandpostionchannelsegmentsoftheligandbindingcore.BioinformanticstudiesplayedakeyroleinthisworkbyrevealingthatiGluRsweremodularproteinsinwhichtheindividualdom
