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1、PostsynapticTargetingofProteinKinasesandPhosphatasesStefanStrackandJohannesW.HellDepartmentofPharmacology,UniversityofIowa,IowaCity,IA52242-1109,USA,stefan-strack@uiowa.edu,johannes-hell@uiowa.edu1IntroductionThediscoveryofanunsuspectednumberofprotein
2、-proteininteractionsduringthepast15yearswasaneyeopenerfortheunanticipateddetailedspatialandfunctionalorganizationofproteinsinsidecells.Colocalizationofproteinkinasesandphosphataseswiththeirregulatorsandsubstratesisofspecialinterestbecauseitiscriticalf
3、orswift,effective,andspecificsignaling(189).Attheplasmamembraneanumberofextracellularsignalsarerelayedwithhighselectivitytospecificintracellularsignalingpathways.Synapsesarerathersmallsubcellularcompartmentsthatfulfillmultiplefunctions:signaltransmiss
4、ionbetweenneurons,processingofneuronalsignals,andstorageofinformation.Targetingmechanismsforkinasesandphosphatasesarethusparticularlyimportantatsynapsestoensurespatialandtemporalfidelityofsignaltransduction.Suchtargetingisnotlimitedtokinasesbutoftenin
5、cludesupstreamregulatorsanddownstreameffectorsofkinases.For2+instance,PKAformsasignalingcomplexwiththepostsynapticL-typeCachannelCav1.2thatcontainsallelementsoftheclassicβ-adrenergic–PKAsignalingcascadeincludingtheβ2adrenergicreceptor,thetrimericGprot
6、einGs,andadenylylcyclase(55,93).Uponactivationoftheβ2adrenergicreceptorandtheensuing2+cAMPproduction,PKAphosphorylatesCav1.2toincreaseitsCachannelactivity.DespiteinvolvingthediffusiblesecondmessengercAMP,signalingfromtheβ2adrenergicreceptorviaPKAtoCav
7、1.2isspatiallyhighlyrestrictedfosteredbytheformationofasupramolecularsignalingcomplex(55).Thischapterdescribesthemolecularbasisandfunctionalrelevanceofpostsynaptickinaseandphosphataseanchoringatglutamatergicsynapses.Glutamateisthemainexcitatoryneurotr
8、ansmitterinthebrain.MostsynapticeventsaremediatedbyAMPA-typeglutamatereceptors.Atemporaryincreaseintransmission2+frequencyleadstoactivationofNMDA-typeglutamatereceptors.TheresultingCainfluxthroughNMDAreceptorscauseslong-term-depression(LTD)atm
