excitatory amino acids. excitatory amino acid receptors transmitter is l-glutamate formed by...
Post on 19-Dec-2015
221 Views
Preview:
TRANSCRIPT
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– ionotropic receptor– opens channel permeable to Na+/K+
– reversal potential ~ 0mV– therefore generates fast EPSP
• Pharmacology– Agonist = AMPA– Antagonist = CNQX
• Molecular biology– Cloned subunits = GluRA-D– similar to nicotinic receptor subunits
H N2 COOHH N2
COOH
– 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
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
• 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
• 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
• 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
• Function– Ca2+ “switch”
• 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
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?
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 N2
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
• 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
Physiological/pathological roles
• Metabotropic glutamate receptors– probably many, including synaptic plasticity
• AMPA receptors– mediate most fast EPSPs in the CNS
• Kainate receptors– anyones guess
• NMDA receptors– Anaesthesia– Learning and memory– Developmental plasticity– Epilepsy– Excitotoxicity (eg stroke)
top related