神经生物学课件Excitatory-Amino-Acids

ExcitatoryAminoAcids2015.10.2720AminoAcidsUsedforProteinSynthesisNon-essential(Ourbodiescanmakethem)AlanineArginineAsparagineAspartateCysteineGlutamateGlycineGlutamineProlineSerineTyrosineEssential(bodycannotmakethemmustgetfromdiet)HistidineIsoleucineLeucineLysineMethioninePhenylalanineThreonineTryptophanValine1.LifeCycleofneurotransmittersBiosynthesis&StorageReleaseReceptorActionInactivation2.BiologicalfunctionsPhysiologyPathologyFluxofionsthroughthechannelsispassiveIntracellularExtracellularNa+Na+Cl-Cl-Ca+Ca+K+K+ATPNa+K+OpeningandclosingofchannelsrequiresconformationalchangeCLOSEDiontransmitterCLOSEDLigand-gatedionchannelsChannelsactivatedbybindingofaligand:AcetylcholinereceptorsSerotoninreceptorsGABAAreceptorsGlycinereceptorsGlutamatereceptorspentamerictetramericSubunitStructureGroupIGABAAGlycine5-HTNicotinicSubunitStructureGroupII AMPAKainateNMDAAminoAcidNTsHighconcentrationinbrain(micromolar)SmallvesiclesPoint-to-pointcommunicationSensory-motorfunctionsConsistentlyexcitatoryorinhibitoryMainlyionotropicreceptorsFastacting,shortduration(1-5ms)1.LifeCycleofglutamateBiosynthesis&StorageReleaseReceptorActionInactivation2.BiologicalfunctionsofglutamatePhysiologyPathologyGlutamatePrincipalexcitatoryNTBiosynthesizedasbyproductofcellmetabolism(Krebscycle)Removedbyreuptake4receptortypesNMDAAMPAKainatemGluRsMetabotropicIonotropicAminoAcidsFormedFrom-Ketoglutarate(酮戊二酸酮戊二酸)Transamination or Glutamate dehydrogenase-Keto-glutarateGlutamateGlutamineGlutamine synthaseGlutaminasePost-synapticNeuronPre-synapticNeuroniGluRTheglutamate:glutamineshuttleEAATGliaGlnEPSPGluGluGluYVesiclelumenH+ATPADP+PiYTvYTcVesicular transportFUNCTIONAccumulation in the presynaptic vesiclesMECHANISMTwo synaptic vesicle proteins mediate the uptake of transmitter:A vacuolar proton pump;A family of transmitter transportersCytosolic transportNATURE REVIEWS|NEUROSCIENCE 2011YProcesses involved in the inactivation of synaptic transmissionProcesses involved in the inactivation of synaptic transmissionYYYYYYUU=uptakeDD=diffusionYZMM=metaboliteYYYYRR=receptordesensitisationOutOutOutIn InInCarrierCarrier(EAAT)(EAAT)K K+CGluGlu2 2 NaNa+(EAAT)=Excitatory amino acid transportersEAAT)=Excitatory amino acid transportersEAAT)=Excitatory amino acid transporters InactivationInactivation EngineEngineATPATPNaNa+K K+Driving forcesDriving forces K K+NaNa+GlutamateuptakeGlutamateuptakeNeuronal/glial(Retinal)Neuronal(cerebellum)NeuronalGlialGlialCellular DistributionEAAT 5EAAT 4EAAC 1EAAT 3GLT-1EAAT 2GLASTEAAT 1Alternative NamesNameTypesofEAATsProbable,primary function:Presynaptic and/or glial neurotransmitter transporters control synaptic levels of neurotransmitterNTGlial cellPresynapticterminalEAAT4 and EAAT5 mediate presynaptic inhibition in cerebellum and retinaPre-synapticNeuroneGluGluhyperpolarisationCl-Cl-Shaping synaptic responses?pH regulation?Reverse transport?But,at synaptic level,glutamate transporters may have other secondary(but potentially important)roles.GLUPresynapticPostsynapticGLUGliaK+Na+Ca2+NMDAAMPAKainateIonotropicMetabotropicGGGlutamate-mediatedsynaptictransmissionSUMMARYGLUTGLUGLUG GGlutamateisaneurotransmitter4 4Binding to receptorsBinding to receptors5 5Functional effectsFunctional effects3 3Uptaken across theUptaken across thecellular membranecellular membrane1 1Concentrated inConcentrated invesiclesvesicles2 2Released byReleased byexocytosisexocytosisASPTASPASPG GIsaspartateaneurotransmitter?4 4Binding to receptorsBinding to receptors5 5Functional effectsFunctional effects3 3Uptaken across theUptaken across thecellular membranecellular membrane1 1Concentrated inConcentrated invesicles?vesicles?2 2Released byReleased byexocytosis?exocytosis?Sialinisavesicularaspartate/glutamatetransporterPNAS 2008 vol.105 11721Proteoliposomes脂蛋白体脂蛋白体ATP谷氨酸受体 I 型 II 型 III 型mGluR-1 mGluR-2 mGluR-4mGluR-5 mGluR-3 mGluR-6 mGluR-7 mGluR-8 Gq/PLC Gi/o/AC Gi/o/AC代谢型受体(mGluR)离子型受体(iGluR)AMPA 受体 KA 受体 NMDA 受体GluA1-4 GluK1-3GluK4-5GluN1GluN2A-DGluN3A-BNa+内流K+外流Na+内流K+外流Na+,Ca2+内流K+外流PostsynapticReceptorsPharmacologyofionotropicglutamatereceptorsGlutamate receptor typeAgonistsAntagonistsAMPAGlutamate,Quisqualate,AMPA(-amino-5-methyl-3-hydoxy-4-isoxazole propionic acid)CNQXNBQXKainateGlutamateKainateCNQXNBQXNMDAGlutamate(also glycine is a co-agonist at a different binding site)NMDA(N-methyl-D-aspartate)AP5(competitive)MK801(ion channel)Dichlorokynurenic acid(at glycine site)AMPAreceptorsandsynapticsignallingqMolecularstructureofAMPAreceptorsqAMPAreceptor-mediatedexcitatorypostsynapticpotential(EPSPs)majorexcitatoryneurotransmitterinCNSaround70%ofallCNSsynapsesareglutamatergicGluA1-4subunitstructureCOOHNH2insideoutsideTM1TM3TM4TM2q LongextracellularaminoterminusqShorterintracellularCterminusqThreetransmembranespanningdomains(TM1,TM3andTM4)qTM2formsare-entryloopwhichlinesthechannelporeqAMPAreceptorsaretetrameric(ie4GluRsubunitscombinetoformreceptor)GluAAMPAreceptorsubunitisoformsGluA1-4IMPERMEABILITYOFAMPARECEPTORSTOCALCIUMGENERATEDBYRNAEDITING（编辑）（编辑）谷胺酰胺谷胺酰胺 CAG(Q)精氨酸精氨酸 CGG(R)ExpressionofAMPAreceptorsubunitsintheratbrainInsituhybridizationinhorizontalbrainsectionsofadultratsDistributionofAMPAreceptorsubunitsinthemousebrainImmunostaininginmousesagittalbrainsectionsGlutamateReceptorsKainateandAMPAreceptorsareverysimilarEPSPsaregeneratedbyNa+influx海人藻酸海人藻酸/红藻氨酸红藻氨酸SynapticresponsestoglutamateusuallyhavebothAMPA-andNMDA-receptormediatedcomponents4outsidecellGlutamateGlycineObligatoryco-agonistZinc(inverseagonist)Polyamine(indirectagonist)2insidecellMagnesium(inverseagonist)PCP(inverseagonist)苯环己哌啶苯环己哌啶 N-methyl-D-aspartate(NMDA)receptors-Unique featuresAs all ligand-operated ion channels,the NMDA-receptor complex has an agonist binding site.OUTINGateAgonistbinding siteGlutamate,NMDA(agonist)But,occupation of the agonist site by NMDA or glutamate is NOT sufficient to open the gate.Ionophore(channel)Gate-opening,requires a second amino acid,glycine,to be present and to bind to an allostericsite on the receptor complex.OUTINAllostericsite forglycineGlutamateNMDAGate-opening,requires a second amino acid,glycine,to be present and to bind to an allostericsite on the receptor complex.OUTINGlycineCo-agonist(activator)GlutamateNMDAAllostericsite forglycine Glycine potentiates the binding of glutamate to its receptor.AllostericmodulationofNMDAreceptorsbyD-serineWhy?OUTINGlycineCo-agonist(activator)GlutamateNMDAWait!You still cant get through.Because,as long as the membrane remains polarised,the pore of the channel is blocked by physiological,extracellular concentration of Mg2+.Mg2+Mg2+Mg2+Mg2+bindingsiteCa2+Na+Ca2+OUTINGlycineCo-agonist(activator)AllostericsiteGlutamateNMDACa2+Na+Ca2+The membrane must be independentlydepolarised to relieve the Mg2+-block and allow ions to flow through.Mg2+IndependentmembranedepolarisationOUTINGlycineCo-agonist(activator)AllostericsiteGlutamateNMDAMg2+Multiple regulatory sitesPolyaminesVoltage-dependentMg2+-blockEndogenouspolyamines(e.g.spermineandspermidine)modulate the NMDA-receptor complex,with low M and high M potentiating and inhibiting its function,respectively.*OUTINGlycineCo-agonist(activator)AllostericsiteGlutamateNMDAMg2+PolyamineMultiple regulatory sitesVoltage-dependentMg2+-blockActivation of intracellular protein kinase C(PKC)enhances NMDA-receptor mediated responses.*Phosphorylation site*GlutamateNMDAMultiple regulatory sitesOUTINGlycineCo-agonist(activator)AllostericsiteMg2+PolyamineVoltage-dependentMg2+-blockPhosphorylation siteRedox site-S=S-*NMDA-receptor mediated responses can be modulated by redox changes,possibly by oxidation and reduction of thiolgroup(s)located within the NMDA-receptor complex.Exposure to reducing agents(e.g.dithiothreitol二硫苏糖醇二硫苏糖醇)potentiates,whereas oxidation reduces NMDA-receptor activation.*NR1NR1NR2NR2?NMDA receptors are large hetero-oligomeric complexes including at least two copies of an NR1 subunit and two copies of an NR2 subunit.NR2NR1GlyGluCa Na2+NMDA receptor subunits NR1 ubiquitous 8 splice forms NR2A forebrain/cerebellumNR2B forebrain/spinal cordNR2C cerebellumNR2D Thalamus/spinal cord NR3A rare in adultNR3B spinal cord Agonist Sensitivity and Deactivation Rates Among NMDA Receptor SubtypesAgonistPotencyNR1/2A NR1/2B NR1/2C NR1/2DGlu1.70.80.70.4Glycine 2.10.30.20.1Off-time,ms503002751700Immature Neurons-higher agonist sensitivity,slower off-rate(NR1/2B,NR1/2D)Mature Neurons-lower agonist sensitivity,faster off-rate(NR1/2A)VOLUME15|NUMBER10|2012TheNMDAGlutamateReceptorRequiresbothNTanddepolarizationtoopenBlockedatRMPbyMg2+DepolarizationdisplacesMg2+ions“LigandandVoltage-dependent”ChannelispermeabletoNa+,K+andCa2+AMPA receptorsNMDA receptorsMg2+ion+Ca2+NMDAandAMPAReceptorsareColocalizedatExcitatorySynapsesBut,thenumberofAMPAreceptorsistightlyregulatedbyactivity,soamplitudeoffastcomponentoftheEPSP/Cscanberapidlyaltered!Fast AMPA component of EPSPSlow NMDA component of EPSP1 mV10 secMetabotropicglutamatereceptorsmGluRsfallintooneofthreecategoriesbasedonsequencehomology,effectormechanismsand,tosomeextent,theirpharmacolgy.PLCACACBraindistributionofmGluRreceptorsMetabotropicglutamtereceptors(Eightdifferentsubtypes)Whenlocalizedtothepresynaptictermianl,inhibitneurotransmtterreleaseWhenlocalizedtothepostsynapticmembrane,exertcomplexmodulatoryeffectsthroughspecificsignaltransductioncascades.FUNCTINALROLESEPILEPSYPAINDEVELOPMENTMEMORYEXCITOTOXICITYAMPAReceptorFunctionGardenvarietyexcitatorysignalsLearningSensoryprocessingPainregulationInductionofseizuresGlutamateReceptorsNature neuroscience 5(9)2002.Spatial memory dissociations In mice lacking GluR1FunctionalConsequencesofGlutamateReceptor/TransporterKnockoutsAMPAreceptors-GluR1-impairedLTP-GluR2-reducedexploratorybehavior,normalorenhancedLTP-GluR2-noQ/Rediting-severeseizures,deathatPN20NMDAReceptorFunctionDevelopmentalPlasticity/LearningIncreasedsynapticdensityincreaseddendriticbranchingincreaseddensityofspinesincreasedneuritesproutingLearning:Long-termDepression(LTD)Long-termPotentiation(LTP)GlutamateReceptorsFunctionalConsequencesofGlutamateReceptor/TransporterKnockoutsNMDAreceptors-NR1,NR2B-earlypost-nataldeath(1day)-respiratoryfailure,feedingimpairment,reducedLTPinhippocampalspecificNR1knockout-NR2A,C,D-normaldevelopment,reducedLTP,impairedmotorcoordinationLongTermPotentiationlasting,activity-dependentincreaseinsynapticefficacy1stobservedbyBliss&Lomo,1973Rabbit hippocampusMayberesponsiblefor:Initial encodingandstorageof memory tracesInitial phases of trace consolidationGreaterthan100moleculeshavebeenimplicatedinLTPandLTDCanlastforhours,days,weeksandinsomecases,monthsDevelopmentallyregulated NMDA-receptor antagonists inhibit the induction of long-term-potentiation(LTP)*LTPisthephenomenonbywhichaspecificpatternofelectricalstimulationofpresynapticinputleadstoapersistentenhancementofsynapticefficiencyTime(min)-100102030EPSP(%change)0153045607590LTP inductionLTP maintenanceMaintenanceofLTP(forhours,days,months)RequiresGenetranscription(CREB)ProteinsynthesisMorphologicalchanges(maybe)EnlargementofdendriticspinesSplittingofspinesfromonetotwohttp:/synapses.mcg.edu/lab/projects.htmOtherformsoflongtermplasticityLongtermdepression(LTD)HippocampusStriatumCerebellumLTDinducedwith1HzstimulationatCA3-CA1synapseThe Journal of Neuroscience,July 1993,13(7):2910-2918NMDAreceptoractivationisrequiredforLTDExcitotoxicity2.WHY,HOWexcessiveglutamatergicactivationishazardoustoneurons?1.Definition:Neuronal excitotoxicity:death of neurones arising from prolonged exposure to glutamate and the associated excessive influx of ions and water into the cell.3.Whichabnormalitiesoftheglutamatergicsynapsemightleadtoexcitotoxicstress/injury?ATPNa+K+Na+Ca2+VoltagegatingCa2+Na+Na+AMPA/Kainate-RNMDA-RCa2+homeostasisE3Na+Ca2+EXCESSIVEEXCESSIVEFUNCTIONINGFUNCTIONINGCa2+i+DepolarisationWe cant copeWe cant copeanymore!anymore!2.WHY,HOW excessive glutamatergic activation is hazardous to neurons?Intracellular Ca2+-overloadCa2+iCaCa2+2+-activated-activated ProteasesProteases(cytoskeleton breakdowncytoskeleton breakdown)PhospholipasesPhospholipases(release of arachidonic acidrelease of arachidonic acid)NOsynthasesNOsynthases EndonucleasesEndonucleases(DNA breakdownDNA breakdown)FreeFreeradicalradicalproductionproductionDeathGLUNa+K+Ca2+VSCCDockingFusionVesicle-+-+Presynaptic abnormalities leading to excessive excitation Where?When?1 13 32 2CellularmembraneGlycineNMDAGlutamateNa+Ca2+OUTOUTININMgMgRedox siteRedox sitePolyaminesPhosphorylation sitePhosphorylation siteIncreased affinity of the glutamate binding sitePostsynapticabnormalitiesPresynapticPostsynapticKainatereceptorsGMetabotropicGIncreased density of glutamate receptorsIncreased expression of kainate receptors in miceinduced pronounced seizure activity.PresynapticPostsynapticGLUNMDA-RAMPA-RKainate-RGGAlteration of the ionic selectivity of glutamate-operated ionophoresCa2+Na+Na+Ca2+Ca2+It has been demonstrated that,in certain conditions,AMPA-R It has been demonstrated that,in certain conditions,AMPA-R(normally Na(normally Na+-permeable)can become permeable to Ca-permeable)can become permeable to Ca2+2+.Deficient glutamate uptakeDeficient glutamate uptake OutOutOutIn InInATPATPNaNa+K K+K K+NaNa+K K+CGluGlu2 2 NaNa+Deficient glutamate uptakeDeficient glutamate uptakeDeficient inactivation ofDeficient inactivation ofglutamatergic transmissionglutamatergic transmissionExcitotoxicityExcitotoxicityDeficient energy supplyDeficient energy supply(ischaemia,mitochondrial damage)(ischaemia,mitochondrial damage)Loss of the Na/K-transmembrane gradientLoss of the Na/K-transmembrane gradient(driving force of the carrier)(driving force of the carrier)PresynapticPostsynapticGliaNMDAAMPAKainateIonotropicreceptorsMetabotropicGGAccumulation of other endogenousGLU-R agonists e.g.Quinolinate对苯二酚对苯二酚NMDA-receptor mediated excitotoxicityControlExposure toNMDA(300 M)for 24 hoursNeurones in cell culture are killed bywhen NMDA receptors are overactivatedFundamental Neuroscience 1999 by M.J.Zigmond,F.E.Bloom,S.C.Landis,J.L.Roberts&L.R.Squire.Academic Press,San Diego CA,USA.ISBN:0-12-780870-1胶质细胞受体兴奋突触后神经元突触前神经元GluGluGluK+Na+GluK+Na+GluGln-KGGluGluGluK+Na+H+ATPADPGln0.5 mmol/LGlu1 mol/LGlu10 mmol/L100 mmol/LSummaryInhibitoryAminoAcidsHistoryGABA(Gamma-AminobutyricAcid)isanaminoacidthatwasfirstdiscoveredin1883inBerlin.In1950,RobertsandAwaparaindependentlydiscoveredthattherewereprodigiousamountsofGABAinthemammaliancentralnervoussystem1mgpergram.In1957,theyfurtherdemonstratedthatchemicallysynthesizedGABAcouldinhibitthecrayfishstretchreceptor(小龙虾牵小龙虾牵张感张感受器受器).-AminobutyricAcid(GABA)HistoryThisobservationpromptedErnstFloreytoproposethatGABAwasactingasaninhibitoryneurotransmitterinthebrain.In1976,HedgecockfoundlysatesfromC.elegansexhibitedenzymaticactivityfortheGABAbiosyntheticenzyme,glutamicaciddecarboxylase(GAD).In1981,GABAAandGABABreceptorspharmacologicallydistinguished.In1987,GABAAreceptorswerecloned.In1990,GABAtransporter1wascloned.In1997,GABABreceptorswerecloned.A)Fluorescentmicrographofanadulthermaphrodite(雌雄同体雌雄同体)stainedwithanantiGABAantiserum.Thereare26neuronsthatstainforGABA.Anterioristotherightandtherightsideofthebodyisshown.Scale bar=0.10 mm.B)Schematicdrawingofthepositionsofthe26GABA-containingneurons.1.LifeCycleofGABABiosynthesis&StorageReleaseReceptorActionInactivation2.BiologicalfunctionsofGABAPhysiologyPathologyGABA(GammaAminobutyricAcid)PrincipalInhibitoryNTBiosynthesis:Removedbyreuptake3receptortypesGABAA(ionotropic)GABAB(metabotropic)GABAC(ionotropic)GluGABAGlutamicAcidDecarboxylase(GAD)andB62SynthesisandMetabolismofGABA琥珀酸琥珀酸延胡索酸延胡索酸苹果酸苹果酸草酰乙酸草酰乙酸异柠檬酸异柠檬酸柠檬酸柠檬酸琥珀酸琥珀酸半醛半醛aa-酮戊二酸酮戊二酸丙酮酸丙酮酸葡萄糖葡萄糖GABAshunt旁路旁路胶质细胞突触后神经元GABA 转运蛋白谷氨酰胺转运蛋白GABAGABA GABA 谷氨酰胺GABA 谷氨酸GABAGSTasesGDH琥珀酸TCA谷氨酸GABA琥珀酸半醛GABA-TSSADHTasesGDHa-酮戊二酸 PAGTCA谷氨酰胺琥珀酸a-酮戊二酸 GABA-TSSADHGAD67GAD65谷氨酸琥珀酸半醛.突触前神经元The life cycle of GABARegulationofGADapoGAD:inactiveenzyme脱辅基酶脱辅基酶holoenzyme:activeenzymewithPLP全酶全酶GAD67:solublecytosolicproteinsaturatedwithPLP(吡哆醛，吡哆醛，B6)GAD65:bothinthecytosolandasmembrane-boundformmajorityoftheapoenzymeSpeciesGeneProteinHumanGAD1(Chr2)GAD67594aaGAD2(Chr10)GAD65585aaMouseGad1(Chr2)GAD67593aaGad2(Chr2)GAD65585aaInhibitorsofGAD:Hydrazides(肼类肼类):interactionwiththeco-factorPLPAllyglycineand3-mercaptopropionicacid3-巯基丙酸巯基丙酸:competitiveinhibitorsGAD67Caudatenucleus：尾状核：尾状核;Corpuscallosum：胼胝体：胼胝体DeficiencyinGAD67:deathsoonafterbirth.GAD65Caudatenucleus：尾状核：尾状核;DeficiencyinGAD65:spontaneousseizures.Atransgenicmousethatexpressesthegreenfluorescentprotein(GFP)inGAD65positiveneurons.bis-benzimide苯甲亚胺苯甲亚胺StorageofGABAVGAT/VIAAT:520aa,10transmembranedomains;ConferringvesicularGABAandglycinetransport;http:/http:/genome.ucsc.eduChaudhryetal.2002JCB.VesicularaccumulationofaminoacidsresultsfrombothagradientofmembranepotentialandpH.GABAReuptakeGATsBelongtoaFamilyofNa+/Cl-dependentNeurotransmitterTransporters(SLC6family)PlasmaMembraneGABATransportersGlycineTransportersDAT,NET,SERTOrphanTransporters GABAReuptakeintheCNSGAT1:mainlyintheneurons,someinglialcells.GAT2:incellsofependymaandarachnoidmembrane(室管膜和室管膜和 蛛网膜蛛网膜)inthebrainandinliver.GAT3:principallyinglia,alsoinsomeneurons.BGT-1:inthebrainandkidney,transportingtheosmolyte(渗透渗透 物物)betaineaswellasGABA.DistributionofGAT-1(A),GAT-2(B),GAT-3(C),VGAT(D),GABA(E)andthionine(亚氨嗪亚氨嗪)-stainedsection(F)inthreeadjacentsectionsofdevelopingSIcortex(感觉皮层感觉皮层)(P5rat).Bar:100mforAE.ABDistributionofGAT-1(A),GAT-2(B),GAT-3(C),GAD67(E),andthethionine-stainedsection(D)inthreeadjacentsectionsofSIcortexinanadultrat.cRNA;mRNATranslationModificationSortingFunctionanalysisReuptake(FunctionsofGATs)AfractionofGATsisstrategicallyplacedtomediateGABAuptakeatfastinhibitorysynapses,terminatingGABAsactionandshapinginhibitorypostsynapticresponses;GATsmaycontributetothedysregulationofneuronalexcitabilitythataccompaniesmajorhumandiseases:epilepsy,ischemia,etc.Tiagabine/Gabitril:硫加宾硫加宾Obviousphenotype:appearanceofspontaneousstrongtremorinGAT1-/-mice A.GAT1(-/-)mice show strong spontaneous tremor,ataxia,andnervousnessGABAReceptorsintheCNSBenzodiazepine sensitive GABAA GABAB GABACNeuronal excitability(seizures)Memory?Rapid changes in mood(anxiety)Mood(depression)Sleep Analgesia痛觉丧失痛觉丧失GABAA receptorsAnionpermeableionchannel(Cl-)Multi-SubunitComplex(pentameric)MajorinhibitorytransmitterinadultbrainTargetformanydrugsandcompoundsGABAABindingSitesGABAMuscimol(蝇蕈醇蝇蕈醇direct agonist);bicuculine(荷包牡丹碱荷包牡丹碱direct antagonist)Benzodiazepine(indirectagonist)Natural inverse agonist binds here(fear,tension,anxiety)Tranquilizing drugs (anxiolytics):valium,librium (安定安定)(利眠宁利眠宁)Likely site for alcohol Barbiturate(indirectagonist)Phenobarbital;pentobarbitalSteroid(indirectagonist)Picrotoxin(Antagonist):印防己毒素印防己毒素 causes convulsionsGABAAreceptorstructurenature reviews|neuroscience2008Table1.GABAAreceptorsubtypesaSubunitsLocalizationPharmacology122Majorsubtype(60%):synapticandextrasynapticBenzodiazepine-sensitive.Mediatessedativeandanticonvulsantactivity232Minorsubtype(1520%):synapticBenzodiazepine-sensitive.Mediatesanxiolyticactivity3n2Minorsubtype(1015%)Benzodiazepine-sensitive.Pharmacologyyetunclear51,32Lessthan5%ofreceptors:extrasynaptic(cerebralcortex,hippocampus,olfactorybulb)Benzodiazepine-sensitive.Mediatesmodulationoftemporalandspatialmemory4nLessthan5%ofreceptors:extrasynapticInsensitivetobenzodiazepines.Sensitivetolowconcentrationofethanol4nLessthan5%ofreceptors:extrasynapticInsensitivetobenzodiazepines6nSmallpopulation:extrasynaptic(onlyincerebellum)Insensitivetobenzodiazepines.Sensitivetolowconcentrationofethanol62,32Lessthan5%ofreceptorssynaptic(onlyincerebellum)InsensitivetobenzodiazepinesaThetermbenzodiazepinereferstodiazepamandstructurallyrelatedagentsinclinicaluse.Subcellular Distribution of GABAA ReceptorsDouble label cell for different GABAA subunits 2/3-10 nm gold particles-synaptic localization-20 nm gold particles-extrasynaptic localization-mouse cerebellumModes of GABAA Receptor ActivationmIPSCeIPSCSynapticExtrasynapticTonicPhasicSynaptic GABA Receptors(EC50 10-20 M)(1,2,3,6)(1,2,3,6)(2,3)(2,3)2 2Subunit Composition of Synaptic and Extrasynaptic GABAA ReceptorsExtrasynapti