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1、ScaffoldProteinsinthePostsynapticDensity123MaryB.Kennedy,EdoardoMarcoraandHollyJ.Carlisle1DivisionofBiology,CaliforniaInstituteofTechnology,Pasadena,CA91125,USA,kennedym@its.caltech.edu2DivisionofBiology,CaliforniaInstituteofTechnology,Pasadena,CA91125,USA,ma
2、rcora@caltech.edu3DivisionofBiology,CaliforniaInstituteofTechnology,Pasadena,CA91125,USA,carlisle@caltech.edu1IntroductionManyintractableneurologicalandmentaldiseases,includingepilepsy,depression,andschizophrenia,arebelievedtoresult,inpart,fromderangementsofr
3、egulationofsynaptictransmissioninthebrain.Forthisreason,muchefforthasbeenmadetodiscoverhowthedelicatemechanismsofsignaltransductionatsynapsesleadtomodificationofsynapticstrength.Onefruitfulareaofresearchoverthelasttwentyyearshasbeenthepostsynapticsignalingapp
4、aratusinglutamatergicspines(8,97,99,106).SpinescontainclustersofreceptorsandsignalingproteinslocatedinadensesubmembranousstructurethatcanbeseenintheelectronmicroscopeandiscalledthepostsynapticdensityorPSD(Forreviewofearlyworksee98).Inthe1970’s,PhilipSiekevitz
5、(40)andCarlCotman(42)workedoutsubcellularfractionationmethodstopurifytinydisksfrombrainthatcontainmanyofthepro-teinsthataremosttightlyboundtothePSD.TheirpurificationmethodswerelaterusedtoobtainmaterialfromwhichseveralubiquitousPSDproteinswereidentifiedandsequ
6、enced,includingtheprototypicalscaffoldprotein,PSD-95(37,109,113),synGAP(35),theshank/proSAPfamily(20),anddensin(6).Atthesametime,andindependently,someoftheseproteins,andadditionalnewonesfromthePSDfrac-tion,wereidentifiedbytheirinteractionsinyeasttwohybridscre
7、ens,includingGKAP(104),synGAP(107),shank/proSAP(158),andhomer(24).ContinuingproteomicanalysesofthePSDfractionorrelated“NMDA-receptorcomplexes”(89,127,177,235)haveproducedacatalogofputativePSD-associatedproteinsthatcomprisesafewhundredindividualproteins.Morere
8、centstudieshavebeguntoaddressthecrucialquestionoftherelativeabundanceofeachproteininthePSDfractionandtheirstoichiometricratios(126,127,177).However,wearestillintheearlystagesofunderstandi
