Excitatory Amino Acids
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Transcript of 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– 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
L-glutamate
+60 mVNa/K/Ca
2pA
20msec0 mV
Na/K/Ca
-60 mV
Na/K/Ca
Mg2+
Mg2+
2pA
20msec
+50-50V (mV)
I (pA)
Mg2+-free
Mg2+
I-V curve
• 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
NMDA
10sec
100pA
NMDA+ CM CM
glycineNMDANMDA
+ glycine
NMDA+ glycine
+ strychnine
• 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)
Summary
• Classification of EAA receptors
• Diversity of actions
• Similarities with other neurotransmitter systems
• Factors modulating NMDA receptors
• Physiological/pathological processes