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

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

6. NMDA receptors Overview –ionotropic receptor –opens channel permeable to Na + /K + /Ca 2+ –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 –Mg 2+ causes a voltage-dependent channel block

10. L-glutamate

11. +60 mV Na/K/Ca 2pA 20msec 0 mV Na/K/Ca -60 mV Na/K/Ca Mg 2+

12. 2pA 20msec +50-50 V (mV) I (pA) Mg 2+ -free Mg 2+ I-V curve

13. Molecular biology –cloned subunits = NR1 & NR2A-D –similar to nicotinic receptor sub-units –form pentamers? –NR1 bestows NMDA receptor-like properties Modulated by –Mg 2+ causes a voltage-dependent channel block – glycine is a cofactor

14. NMDA 10sec 100pA NMDA + CM CM glycineNMDA + glycine NMDA + glycine + strychnine

15. Molecular biology –cloned subunits = NR1 & NR2A-D –similar to nicotinic receptor sub-units –form pentamers? –NR1 bestows NMDA receptor-like properties Modulated by –Mg 2+ causes a voltage-dependent channel block – glycine is a cofactor – ketamine/phencyclidine/MK801 block ion channel

16. Function –Ca 2+ “switch” Molecular biology –cloned subunits = NR1 & NR2A-D –similar to nicotinic receptor sub-units –form pentamers? –NR1 bestows NMDA receptor-like properties Modulated by –Mg 2+ causes a voltage-dependent channel block – glycine is a cofactor – ketamine/phencyclidine/MK801 block ion channel

17. 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?

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

19. Metabotropic glutamate receptors – 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 Overview –g-protein coupled positively linked to PLC negatively linked to adenylate cyclase or direct to ion channels Molecular biology

20. 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 I AHP –blocks M-current (therefore evokes slow EPSP) –blocks voltage dependent Ca 2+ channels Functions –Neuromodulator - analgous to ACh muscarinic receptors

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

22. NMDA receptors –Anaesthesia –Learning and memory –Developmental plasticity –Epilepsy –Excitotoxicity (eg stroke)

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