Role of the Proteasome in Excitotoxicity-Induced Cleavage of Glutamic Acid Decarboxylase in Cultured Hippocampal Neurons 英文参考文献.docVIP

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Role of the Proteasome in Excitotoxicity-Induced Cleavage of Glutamic Acid Decarboxylase in Cultured Hippocampal Neurons 英文参考文献.doc

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Role of the Proteasome in Excitotoxicity-Induced Cleavage of Glutamic Acid Decarboxylase in Cultured Hippocampal Neurons 英文参考文献

RoleoftheProteasomeinExcitotoxicity-Induced CleavageofGlutamicAcidDecarboxylaseinCultured HippocampalNeurons Ma′rcioS.Baptista1.,CarlosV.Melo1*.¤a,Ma′rioArmela?o1,DennisHerrmann1,DiogoO.Pimentel1, GracianoLeal1,MargaridaV.Caldeira1,BenA.Bahr2,Ma′rioBengtson3¤b,RamiroD.Almeida1,CarlosB. Duarte1 1Center for Neuroscience and Cell Biology, Department of Life Sciences, University of Coimbra, Coimbra, Portugal, 2Biotechnology Research and Training Center, UniversityofNorthCarolina,Pembroke,NorthCarolina,UnitedStatesofAmerica,3DepartmentofCancerandCellBiology,GenomicsInstituteoftheNovartisResearch Foundation(GNF),SanDiego,California,UnitedStatesofAmerica Abstract GlutamicaciddecarboxylaseisresponsibleforsynthesizingGABA,themajorinhibitoryneurotransmitter,andexistsintwo isoforms—GAD65andGAD67.Theenzymeiscleavedunderexcitotoxicconditions,butthemechanismsinvolvedandthe functionalconsequencesarenotfullyelucidated.Wefoundthatexcitotoxicstimulationofculturedhippocampalneurons withglutamateleads toatime-dependentcleavage ofGAD65andGAD67 intheN-terminal region oftheproteins, and decreasethecorrespondingmRNAs.ThecleavageofGAD67wassensitivetotheproteasomeinhibitorsMG132,YU102and lactacystin,andwasalsoabrogatedbytheE1ubiquitinligaseinhibitorUBEI-41.Incontrast,MG132andUBEI-41werethe onlyinhibitorstestedthatshowedaneffectonGAD65cleavage.Excitotoxicstimulationwithglutamatealsoincreasedthe amountofGADcapturedinexperimentswhereubiquitinatedproteinsandtheirbindingpartnerswereisolated.However, noevidenceswerefoundfordirectGADsubiquitinationinculturedhippocampalneurons,andrecombinantGAD65wasnot cleavedbypurified20Sor26Sproteasomepreparations.Sincecalpains,agroupofcalciumactivatedproteases,playakey roleinGAD65/67cleavageunderexcitotoxicconditionstheresultssuggestthatGADsarecleavedafterubiquitinationand degradationofanunknownbindingpartnerbytheproteasome.ThecharacteristicpunctatedistributionofGAD65along neuritesofdifferentiatedculturedhippocampalneuronswassignificantlyreducedafterexcitoto