神经生物学课件：Excitatory Amino Acids

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1、Excitatory Amino Acids20 Amino Acids Used for Protein Synthesis Non-essential(Our bodies can make them)Alanine Arginine Asparagine Aspartate Cysteine Glutamate Glycine Glutamine Proline Serine Tyrosine Essential(body cannot make them must get from diet)Histidine Isoleucine Leucine Lysine Methionine

2、Phenylalanine Threonine Tryptophan Valine1.Life Cycle of neurotransmitters Biosynthesis&Storage Release Receptor Action Inactivation2.Biological functions Physiology PathologyFlux of ions through the channels is passiveIntracellularExtracellularNa+Na+Cl-Cl-Ca+Ca+K+K+ATPNa+K+Opening and closing of ch

3、annels requires conformational changeCLOSEDiontransmitterCLOSEDLigand-gated ion channelsChannels activated by binding of a ligand:Acetylcholine receptors Serotonin receptors GABAA receptors Glycine receptors Glutamate receptorspentamerictetramericSubunit Structure Group IGABAAGlycine5-HTNicotinicSub

4、unit Structure Group II AMPAKainateNMDAAmino Acid NTs High concentration in brain(micromolar)Small vesicles Point-to-point communication Sensory-motor functions Consistently excitatory or inhibitory Mainly ionotropic receptors Fast acting,short duration(1-5 ms)1.Life Cycle of glutamate Biosynthesis&

5、Storage Release Receptor Action Inactivation2.Biological functions of glutamate Physiology PathologyGlutamate Principal excitatory NT Biosynthesized as byproduct of cell metabolism(Krebs cycle)Removed by reuptake 4 receptor types NMDA AMPA Kainate mGluRs Metabotropic IonotropicAmino Acids Formed Fro

6、m a a-Ketoglutarate(酮戊二酸酮戊二酸)O-O2CCH2CH2CCO2-NH3+-O2CCH2CH2CHCO2-NH3+OH2NCCH2CH2CHCO2-Transamination or Glutamate dehydrogenasea a-Keto-glutarateGlutamateGlutamineGlutamine synthaseGlutaminasePost-synapticNeuronPre-synapticNeuroniGluRThe glutamate:glutamine shuttle EAATGliaGlnEPSPGluGluGluYVesiclelu

7、menH+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 ina

8、ctivation of synaptic transmissionYYYYYYUU=uptakeDD=diffusionYZMM=metaboliteYYYYRR=receptordesensitisation Neuronal/glial(Retinal)Neuronal(cerebellum)NeuronalGlialGlialCellular DistributionEAAT 5EAAT 4EAAC 1EAAT 3GLT-1EAAT 2GLASTEAAT 1Alternative NamesNameTypes of EAATsProbable,primary function:Pres

9、ynaptic 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 transpo

10、rt?But,at synaptic level,glutamate transporters may have other secondary(but potentially important)roles.GLUPresynapticPostsynapticGLUGliaK+Na+Ca2+NMDAAMPAKainateIonotropicMetabotropicGG Glutamate-mediated synaptic transmissionSUMMARYGLUTGLUGLUGlutamate is a neurotransmitterASPTASPASPIs aspartate a

11、neurotransmitter?Sialin is a vesicular aspartate/glutamate transporterPNAS 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-8Gq/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 GluK1-3GluK4-5GluN1GluN2

12、A-DGluN3A-BNa+内流K+外流Na+内流K+外流Na+,Ca2+内流K+外流Postsynaptic ReceptorsPharmacology of ionotropic glutamate receptorsGlutamate receptor typeAgonistsAntagonistsAMPAGlutamate,Quisqualate,AMPA(-amino-5-methyl-3-hydoxy-4-isoxazole propionic acid)CNQXNBQXKainateGlutamateKainateCNQXNBQXNMDAGlutamate(also glycin

13、e is a co-agonist at a different binding site)NMDA(N-methyl-D-aspartate)AP5(competitive)MK801(ion channel)Dichlorokynurenic acid(at glycine site)AMPA receptors and synaptic signallingq Molecular structure of AMPA receptorsq AMPA receptor-mediated excitatory post synaptic potential(EPSPs)major excita

14、tory neurotransmitter in CNS around 70%of all CNS synapses are glutamatergicGluA1-4 subunit structureCOOHNH2insideoutsideTM1TM3TM4TM2q Long extracellular amino terminusq Shorter intracellular C terminusq Three transmembrane spanning domains(TM1,TM3 and TM4)q TM2 forms a re-entry loop which lines the

15、 channel poreq AMPA receptors are tetrameric (ie 4 GluR subunits combine to form receptor)GluAAMPA receptor subunit isoformsGluA1-4IMPERMEABILITY OF AMPA RECEPTORS TO CALCIUM GENERATED BY RNA EDITING（编辑）（编辑）谷胺酰胺谷胺酰胺 CAG(Q)精氨酸精氨酸 CGG(R)Expression of AMPA receptor subunits in the rat brainIn situ hybr

16、idization in horizontalbrain sections of adult ratsDistribution of AMPA receptor subunits in the mouse brainImmunostaining in mouse sagittal brain sectionsGlutamate Receptors Kainate and AMPA receptors are very similar EPSPs are generated by Na+influx海人藻酸海人藻酸/红藻氨酸红藻氨酸Synaptic responses to glutamate

17、usually have both AMPA-and NMDA-receptor mediated components 4 outside cell Glutamate Glycine Obligatory co-agonist Zinc(inverse agonist)Polyamine(indirect agonist)2 inside cell Magnesium(inverse agonist)PCP(inverse agonist)苯环己哌啶苯环己哌啶 N-methyl-D-aspartate(NMDA)receptors-Unique featuresAs all ligand-

18、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

19、and to bind to an allosteric site on the receptor complex.OUTINAllostericsite forglycineGlutamateNMDAGate-opening,requires a second amino acid,glycine,to be present and to bind to an allosteric site on the receptor complex.OUTINGlycineCo-agonist(activator)GlutamateNMDAAllostericsite forglycine Glyci

20、ne potentiates the binding of glutamate to its receptor.Allosteric modulation of NMDA receptors by D-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,extracell

21、ular concentration of Mg2+.Mg2+Mg2+Mg2+Mg2+bindingsiteCa2+Na+Ca2+OUTINGlycineCo-agonist(activator)AllostericsiteGlutamateNMDACa2+Na+Ca2+The membrane must be independently depolarised to relieve the Mg2+-block and allow ions to flow through.Mg2+IndependentmembranedepolarisationOUTINGlycineCo-agonist(

22、activator)AllostericsiteGlutamateNMDAMg2+Multiple regulatory sitesPolyaminesVoltage-dependentMg2+-blockEndogenous polyamines(e.g.spermine and spermidine)modulate the NMDA-receptor complex,with low M and high M potentiating and inhibiting its function,respectively.*OUTINGlycineCo-agonist(activator)Al

23、lostericsiteGlutamateNMDAMg2+PolyamineMultiple regulatory sitesVoltage-dependentMg2+-blockActivation of intracellular protein kinase C(PKC)enhances NMDA-receptor mediated responses.*Phosphorylation site*GlutamateNMDAMultiple regulatory sitesOUTINGlycineCo-agonist(activator)AllostericsiteMg2+Polyamin

24、eVoltage-dependentMg2+-blockPhosphorylation siteRedox site-S=S-*NMDA-receptor mediated responses can be modulated by redox changes,possibly by oxidation and reduction of thiol group(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,wherea

25、s 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 foreb

26、rain/spinal cordNR2C cerebellumNR2D Thalamus/spinal cord NR3A rare in adultNR3B spinal cord Agonist Sensitivity and Deactivation Rates Among NMDA Receptor SubtypesAgonist PotencyNR1/2A NR1/2B NR1/2C NR1/2DGlu1.70.80.70.4Glycine 2.10.30.20.1Off-time,ms503002751700Immature Neurons-higher agonist sensi

27、tivity,slower off-rate(NR1/2B,NR1/2D)Mature Neurons-lower agonist sensitivity,faster off-rate(NR1/2A)VOLUME 15|NUMBER 10|2012The NMDA Glutamate Receptor Requires both NT and depolarization to open Blocked at RMP by Mg2+Depolarization displaces Mg2+ions“Ligand and Voltage-dependent”Channel is permeab

28、le to Na+,K+and Ca2+AMPA receptorsNMDA receptorsMg2+ion+Ca2+NMDA and AMPA Receptors are Colocalized at Excitatory SynapsesBut,the number of AMPA receptors is tightly regulated by activity,soamplitude of fast component of the EPSP/Cs can be rapidly altered!Fast AMPA component of EPSPSlow NMDA compone

29、nt of EPSP1 mV10 secMetabotropic glutamate receptorsmGluRs fall into one of three categories based on sequence homology,effector mechanisms and,to some extent,their pharmacolgy.PLCACACBrain distribution of mGluR receptorsMetabotropic glutamte receptors (Eight different subtypes)When localized to the

30、 presynaptic termianl,inhibit neurotransmtter releaseWhen localized to the postsynaptic membrane,exert complex modulatory effects through specific signal transduction cascades.FUNCTINAL ROLES EPILEPSY PAIN DEVELOPMENT MEMORY EXCITOTOXICITYAMPA Receptor Function Garden variety excitatory signalsLearn

31、ingSensory processingPain regulationInduction of seizuresGlutamate ReceptorsNature neuroscience 5(9)2002.Spatial memory dissociations In mice lacking GluR1Functional Consequences of Glutamate Receptor/Transporter KnockoutsAMPA receptors-GluR1-impaired LTP-GluR2-reduced exploratory behavior,normal or

32、 enhanced LTP-GluR2-no Q/R editing-severe seizures,death at PN20NMDA Receptor Function Developmental Plasticity/LearningIncreased synaptic density increased dendritic branching increased density of spines increased neurite sproutingLearning:Long-term Depression(LTD)Long-term Potentiation(LTP)Glutama

33、te ReceptorsFunctional Consequences of Glutamate Receptor/Transporter KnockoutsNMDA receptors-NR1,NR2B-early post-natal death(1 day)-respiratory failure,feeding impairment,reduced LTP in hippocampal specific NR1 knockout-NR2A,C,D-normal development,reduced LTP,impaired motor coordinationLong Term Po

34、tentiationlasting,activity-dependent increase in synaptic efficacy 1st observed by Bliss&Lomo,1973 Rabbit hippocampus May be responsible for:Initial encoding and storage of memory traces Initial phases of trace consolidation Greater than 100 molecules have been implicated in LTP and LTD Can last for

35、 hours,days,weeks and in some cases,months Developmentally regulated NMDA-receptor antagonists inhibit the induction of long-term-potentiation(LTP)*LTP is the phenomenon by which a specific pattern of electrical stimulation of presynaptic input leads to a persistent enhancement of synaptic efficienc

36、yTime(min)-100102030EPSP(%change)0153045607590LTP inductionLTP maintenanceMaintenance of LTP(for hours,days,months)Requires Gene transcription(CREB)Protein synthesis Morphological changes(maybe)Enlargement of dendritic spines Splitting of spines from one to twohttp:/synapses.mcg.edu/lab/projects.htm

37、Other forms of long term plasticity Long term depression(LTD)Hippocampus Striatum CerebellumLTD induced with 1 Hz stimulation at CA3-CA1 synapseThe Journal of Neuroscience,July 1993,13(7):2910-2918NMDA receptor activation is required for LTDExcitotoxicity2.WHY,HOW excessive glutamatergic activation

38、is hazardous to neurons?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.Which abnormalities of the glutamatergic synapse might lead to excitotoxic stress/injury?ATPVoltagegatingA

39、MPA/Kainate-RNMDA-RCa2+homeostasisE2.WHY,HOW excessive glutamatergic activation is hazardous to neurons?Intracellular Ca2+-overloadDeathGLUNa+K+Ca2+VSCCDockingFusionVesiclePresynaptic abnormalities leading to excessive excitationCellularmembraneGlycineNMDAGlutamateNa+Ca2+OUTINPolyaminesIncreased aff

40、inity of the glutamate binding sitePostsynapticabnormalitiesPresynapticPostsynapticKainatereceptorsGMetabotropicGIncreased density of glutamate receptorsIncreased expression of kainate receptors in miceinduced pronounced seizure activity.PresynapticPostsynapticGLUNMDA-RAMPA-RKainate-RGGAlteration of

41、 the ionic selectivity of glutamate-operated ionophoresCa2+Na+Na+Ca2+Ca2+PresynapticPostsynapticGliaNMDAAMPAKainateIonotropicreceptorsMetabotropicGGAccumulation of other endogenousGLU-R agonists e.g.Quinolinate对苯二酚对苯二酚NMDA-receptor mediated excitotoxicityControlExposure toNMDA(300 m mM)for 24 hoursN

42、eurones 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/LG

43、lu1 mol/LGlu10 mmol/L100 mmol/LSummary Inhibitory Amino Acids History GABA(Gamma-Aminobutyric Acid)is an amino acid that was first discovered in 1883 in Berlin.In 1950,Roberts and Awapara independently discovered that there were prodigious amounts of GABA in the mammalian central nervous system 1 mg

44、 per gram.In 1957,they further demonstrated that chemically synthesized GABA could inhibit the crayfish stretch receptor(小龙虾牵张感小龙虾牵张感 受受器器).-Aminobutyric Acid(GABA)History This observation prompted Ernst Florey to propose that GABA was acting as an inhibitory neurotransmitter in the brain.In 1976,He

45、dgecock found lysates from C.elegans exhibited enzymatic activity for the GABA biosynthetic enzyme,glutamic acid decarboxylase(GAD).In 1981,GABAA and GABAB receptors pharmacologically distinguished.In 1987,GABAA receptors were cloned.In 1990,GABA transporter 1 was cloned.In 1997,GABAB receptors were

46、 cloned.A)Fluorescent micrograph of an adult hermaphrodite(雌雄同体雌雄同体)stained with an antiGABA antiserum.There are 26 neurons that stain for GABA.Anterior is to the right and the right side of the body is shown.Scale bar=0.10 mm.B)Schematic drawing of the positions of the 26 GABA-containing neurons.1.

47、Life Cycle of GABA Biosynthesis&Storage Release Receptor Action Inactivation2.Biological functions of GABA Physiology PathologyGABA(Gamma Aminobutyric Acid)Principal Inhibitory NT Biosynthesis:Removed by reuptake 3 receptor types GABAA(ionotropic)GABAB(metabotropic)GABAC(ionotropic)GluGABAGlutamic A

48、cidDecarboxylase(GAD)and B62Synthesis and Metabolism of GABA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a-酮戊二酸酮戊二酸丙酮酸丙酮酸葡萄糖葡萄糖GABA shunt 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-TSSADHGAD67GAD6

49、5谷氨酸琥珀酸半醛.突触前神经元The life cycle of GABARegulation of GADapoGAD:inactive enzyme脱辅基酶脱辅基酶holoenzyme:active enzyme with PLP 全酶全酶GAD67:soluble cytosolic protein saturated with PLP (吡哆醛，吡哆醛，B6)GAD65:both in the cytosol and as membrane-bound form majority of the apoenzymeSpeciesGeneProteinHumanGAD1(Chr 2)GA

50、D67594aaGAD2(Chr 10)GAD65585aaMouseGad1(Chr 2)GAD67593aaGad2(Chr 2)GAD65 585aaInhibitors of GAD:Hydrazides(肼类肼类):interaction with the co-factor PLPAllyglycine and 3-mercaptopropionic acid 3-巯基丙酸巯基丙酸:competitive inhibitors GAD67Caudate nucleus：尾状核：尾状核;Corpus callosum：胼胝体：胼胝体Deficiency in GAD67:death

51、soon after birth.GAD65Caudate nucleus：尾状核：尾状核;Deficiency in GAD65:spontaneous seizures.A transgenic mousethat expresses thegreen fluorescentprotein(GFP)in GAD65 positive neurons.bis-benzimide苯甲亚胺苯甲亚胺Storage of GABAVGAT/VIAAT:520aa,10 transmembrane domains;Conferring vesicular GABA and glycine transp

52、ort;http:/http:/genome.ucsc.eduChaudhry et al.2002 JCB.Vesicular accumulationof amino acids results from both a gradient of membrane potential and pH.GABA ReuptakeGATs Belong to a Family of Na+/Cl-dependent Neurotransmitter Transporters(SLC6 family)Plasma MembraneGABA TransportersGlycine Transporter

53、sDAT,NET,SERTOrphan Transporters GABA Reuptake in the CNSGAT1:mainly in the neurons,some in glial cells.GAT2:in cells of ependyma and arachnoid membrane(室管膜和室管膜和 蛛网膜蛛网膜)in the brain and in liver.GAT3:principally in glia,also in some neurons.BGT-1:in the brain and kidney,transporting the osmolyte(渗透渗

54、透 物物)betaine as well as GABA.Distribution of GAT-1(A),GAT-2(B),GAT-3(C),VGAT(D),GABA(E)and thionine(亚氨嗪亚氨嗪)-stained section(F)in three adjacent sections of developing SI cortex(感觉皮层感觉皮层)(P5 rat).Bar:100 m for AE.ABDistribution of GAT-1(A),GAT-2(B),GAT-3(C),GAD67(E),and the thionine-stained section(D

55、)in three adjacent sections of SI cortex in an adult rat.cRNA;mRNATranslationModificationSortingFunction analysisReuptake(Functions of GATs)A fraction of GATs is strategically placed to mediate GABA uptake at fast inhibitory synapses,terminating GABAs action and shaping inhibitory postsynaptic respo

56、nses;GATs may contribute to the dysregulation of neuronal excitability that accompanies major human diseases:epilepsy,ischemia,etc.Tiagabine/Gabitril:硫加宾硫加宾Obvious phenotype:appearance of spontaneous strong tremor in GAT1-/-mice A.GAT1(-/-)mice show strong spontaneous tremor,ataxia,andnervousnessGAB

57、A Receptors in the CNSBenzodiazepine 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 receptorsAnion permeable ion channel(Cl-)Multi-Subunit Complex(pentameric)Major inhibitory transmitter in adult brainTarget

58、 for many drugs and compoundsGABAA Binding SitesGABA Muscimol(蝇蕈醇蝇蕈醇direct agonist);bicuculine(荷包牡丹碱荷包牡丹碱 direct antagonist)Benzodiazepine(indirect agonist)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 B

59、arbiturate(indirect agonist)Phenobarbital;pentobarbitalSteroid(indirect agonist)Picrotoxin(Antagonist):印防己毒素印防己毒素 causes convulsionsGABAA receptor structurenature reviews|neuroscience 2008Table 1.GABAA receptor subtypesa SubunitsLocalizationPharmacology122Major subtype(60%):synaptic and extrasynapti

60、cBenzodiazepine-sensitive.Mediates sedative and anticonvulsant activity232Minor subtype(1520%):synapticBenzodiazepine-sensitive.Mediates anxiolytic activity3n2Minor subtype(1015%)Benzodiazepine-sensitive.Pharmacology yet unclear51,32Less than 5%of receptors:extrasynaptic(cerebral cortex,hippocampus,

61、olfactory bulb)Benzodiazepine-sensitive.Mediates modulation of temporal and spatial memory4nLess than 5%of receptors:extrasynapticInsensitive to benzodiazepines.Sensitive to low concentration of ethanol4nLess than 5%of receptors:extrasynapticInsensitive to benzodiazepines6nSmall population:extrasyna

62、ptic(only in cerebellum)Insensitive to benzodiazepines.Sensitive to low concentration of ethanol62,32Less than 5%of receptors synaptic(only in cerebellum)Insensitive to benzodiazepinesa The term benzodiazepine refers to diazepam and structurally related agents in clinical use.Subcellular Distributio

63、n 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 mM)a a(1,

64、2,3,6)(1,2,3,6)(2,3)(2,3)2 2Subunit Composition of Synaptic and Extrasynaptic GABAA ReceptorsExtrasynaptic GABA Receptors(EC50 0.5 m mM)Cerebellar granule neurons a a6 6(2,3)(2,3)Thalamus,dentate gyrusa a Hippocampal pyramidala a5 5 3 3 2 2Excitatory Effects of GABA in Immature NeuronsHippocampal sl

65、ices/pyramidal neuronsStimulus elicits 4 post-synaptic responsesTwo of these are blocked by AMPA and NMDA antagonistsThe remaining two are blocked by GABAA antagonist bicucullineSo GABAA receptors can excite neurons also-how?NKCC1 Na+K+2Cl-GABAB Receptors First suspected in 1981;l-baclofen(-对氯对氯 苯基苯

66、基-氨基丁酸氨基丁酸 肌松药肌松药)induced responses not blocked by bicucculine,the GABAA antagonist Expression cloning in oocytes not successful cDNA isolated in 1997Neuropharmacology 60(2011)GABAB Actions GABABGK+Postsynaptic Presynaptic GABABGCa+GABAGABA GABAC ReceptorLigand-gated Cl-channel(similar to GABA-A)Not a target of benzodiazepines,barbiturates,ethanolPhysiologic role less clear(at present)Pharmacology and Structure of GABAc ReceptorsCis-4-transamino crotonic acid:反反-丁烯酸丁烯酸TPMPA：1,2,5,6-四氢吡啶四氢吡啶-4-基基