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