Excitatory Amino Acids

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Excitatory Amino Acids. Excitatory amino acid receptors. Transmitter is L-glutamate Formed by GABA-transaminase Inactivated by uptake Receptor classification based on electrophysiology, binding & cloning Nomenclature - NMDA, AMPA, kainate, metabotropic. AMPA receptors. Overview - PowerPoint PPT Presentation

Text of Excitatory Amino Acids

  • Excitatory Amino Acids

  • Excitatory amino acid receptorsTransmitter is L-glutamateFormed by GABA-transaminaseInactivated by uptakeReceptor classification based onelectrophysiology, binding & cloningNomenclature - NMDA, AMPA, kainate, metabotropic

  • AMPA receptorsOverviewionotropic receptoropens channel permeable to Na+/K+reversal potential ~ 0mVtherefore generates fast EPSPPharmacologyAgonist = AMPAAntagonist = CNQX

  • Molecular biologyCloned subunits = GluRA-Dsimilar to nicotinic receptor subunits

  • form pentamers? GluRB bestows AMPA receptor-like properties Functionnicotinic-likemediates most fast excitatory transmissionMolecular biologyCloned subunits = GluRA-Dsimilar to nicotinic receptor subunits

  • NMDA receptorsOverviewionotropic receptoropens channel permeable to Na+/K+/Ca2+reversal potential ~ 0mVtherefore generates fast(-ish) EPSPPharmacologyagonist = NMDAantagonist = AP5

  • Molecular biologycloned subunits = NR1 & NR2A-Dsimilar to nicotinic receptor sub-unitsform pentamers?NR1 bestows NMDA receptor-like propertiesModulated byMg2+ causes a voltage-dependent channel block

  • I-V curve

  • Molecular biologycloned subunits = NR1 & NR2A-Dsimilar to nicotinic receptor sub-unitsform pentamers?NR1 bestows NMDA receptor-like propertiesModulated byMg2+ causes a voltage-dependent channel block

    glycine is a cofactor

  • Molecular biologycloned subunits = NR1 & NR2A-Dsimilar to nicotinic receptor sub-unitsform pentamers?NR1 bestows NMDA receptor-like propertiesModulated byMg2+ causes a voltage-dependent channel block

    glycine is a cofactor

    ketamine/phencyclidine/MK801 block ion channel

  • FunctionCa2+ switchMolecular biologycloned subunits = NR1 & NR2A-Dsimilar to nicotinic receptor sub-unitsform pentamers?NR1 bestows NMDA receptor-like propertiesModulated byMg2+ causes a voltage-dependent channel block

    glycine is a cofactor

    ketamine/phencyclidine/MK801 block ion channel

  • Kainate receptorsConfusion over identificationkainate activates AMPA receptorspart of kainate binding is not displaced by AMPAMolecular BiologyCloned subunits = KA1-2 & GluR5-7form pentamers?rapidly desensitising (AMPA insensitive) channelFunction?

  • Metabotropic glutamate receptorsOverviewg-protein coupledpositively linked to PLCnegatively linked to adenylate cyclaseor direct to ion channelsMolecular biology

  • Metabotropic glutamate receptors mGluR 1-8Group I = mGluR 1&5 linked to PLCGroup II = mGluR 2&3 linked to adenylate cyclaseGroup III = mGluR 4&6-8 linked to adenylate cyclaseOverviewg-protein coupledpositively linked to PLCnegatively linked to adenylate cyclaseor direct to ion channelsMolecular biology

  • Pharmacologymost commonly used agonist = (1S,3R) ACPDis selective for Group I and Group IImost commonly used antagonist = MCPGnon-selective antagonist?Electrophysiological actionsblocks IAHPblocks M-current (therefore evokes slow EPSP)blocks voltage dependent Ca2+ channels FunctionsNeuromodulator - analgous to ACh muscarinic receptors

  • Physiological/pathological rolesMetabotropic glutamate receptorsprobably many, including synaptic plasticityAMPA receptorsmediate most fast EPSPs in the CNSKainate receptorsanyones guess

  • NMDA receptorsAnaesthesiaLearning and memoryDevelopmental plasticityEpilepsyExcitotoxicity (eg stroke)

  • SummaryClassification of EAA receptorsDiversity of actions Similarities with other neurotransmitter systemsFactors modulating NMDA receptorsPhysiological/pathological processes