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Excitatory Amino Acids

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

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Excitatory Amino Acids

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  1. Excitatory Amino Acids

  2. 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

  3. AMPA receptors • Overview • ionotropic receptor • opens channel permeable to Na+/K+ • reversal potential ~ 0mV • therefore generates fast EPSP • Pharmacology • Agonist = AMPA • Antagonist = CNQX

  4. H N H N 2 2 COOH COOH • Molecular biology • Cloned subunits = GluRA-D • similar to nicotinic receptor subunits

  5. Molecular biology • Cloned subunits = GluRA-D • similar to nicotinic receptor subunits • form pentamers? • GluRB bestows AMPA receptor-like properties • Function • nicotinic-like • mediates most fast excitatory transmission

  6. NMDA receptors • Overview • ionotropic receptor • opens channel permeable to Na+/K+/Ca2+ • reversal potential ~ 0mV • therefore generates fast(-ish) EPSP • Pharmacology • agonist = NMDA • antagonist = AP5

  7. Molecular biology • cloned subunits = NR1 & NR2A-D • similar to nicotinic receptor sub-units • form pentamers? • NR1 bestows NMDA receptor-like properties • Modulated by • Mg2+ causes a voltage-dependent channel block

  8. L-glutamate

  9. Mg2+ +60 mV • Na/K/Ca 2pA 20msec 0 mV • Na/K/Ca -60 mV Na/K/Ca Mg2+

  10. I (pA) 2pA 20msec V (mV) -50 +50 Mg2+ Mg2+-free I-V curve

  11. Molecular biology • cloned subunits = NR1 & NR2A-D • similar to nicotinic receptor sub-units • form pentamers? • NR1 bestows NMDA receptor-like properties • Modulated by • Mg2+ causes a voltage-dependent channel block • glycine is a cofactor

  12. NMDA + CM NMDA CM 100pA 10sec NMDA + glycine + strychnine NMDA + glycine NMDA glycine

  13. Molecular biology • cloned subunits = NR1 & NR2A-D • similar to nicotinic receptor sub-units • form pentamers? • NR1 bestows NMDA receptor-like properties • Modulated by • Mg2+ causes a voltage-dependent channel block • glycine is a cofactor • ketamine/phencyclidine/MK801 block ion channel

  14. Molecular biology • cloned subunits = NR1 & NR2A-D • similar to nicotinic receptor sub-units • form pentamers? • NR1 bestows NMDA receptor-like properties • Modulated by • Mg2+ causes a voltage-dependent channel block • Function • Ca2+ “switch” • glycine is a cofactor • ketamine/phencyclidine/MK801 block ion channel

  15. Kainate receptors • Confusion over identification • kainate activates AMPA receptors • part of kainate binding is not displaced by AMPA • Molecular Biology • Cloned subunits = KA1-2 & GluR5-7 • form pentamers? • rapidly desensitising (AMPA insensitive) channel • Function?

  16. H N 2 COOH Metabotropic glutamate receptors • Overview • g-protein coupled • positively linked to PLC • negatively linked to adenylate cyclase • or direct to ion channels • Molecular biology

  17. Metabotropic glutamate receptors • Overview • g-protein coupled • positively linked to PLC • negatively linked to adenylate cyclase • or direct to ion channels • Molecular biology • mGluR 1-8 • Group I = mGluR 1&5 linked to PLC • Group II = mGluR 2&3 linked to adenylate cyclase • Group III = mGluR 4&6-8 linked to adenylate cyclase

  18. Pharmacology • most commonly used agonist = (1S,3R) ACPD • is selective for Group I and Group II • most commonly used antagonist = MCPG • non-selective antagonist? • Electrophysiological actions • blocks IAHP • blocks M-current (therefore evokes slow EPSP) • blocks voltage dependent Ca2+ channels • Functions • Neuromodulator - analgous to ACh muscarinic receptors

  19. Physiological/pathological roles • Metabotropic glutamate receptors • probably many, including synaptic plasticity • AMPA receptors • mediate most fast EPSPs in the CNS • Kainate receptors • anyones guess

  20. NMDA receptors • Anaesthesia • Learning and memory • Developmental plasticity • Epilepsy • Excitotoxicity (eg stroke)

  21. Summary • Classification of EAA receptors • Diversity of actions • Similarities with other neurotransmitter systems • Factors modulating NMDA receptors • Physiological/pathological processes

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