Download Excitatory amino acid receptors

Excitatory
Amino Acids
Excitatory amino acid receptors
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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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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 N
2
COOH
H2N
COOH
• 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
NMDA receptors
• Overview
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ionotropic receptor
opens channel permeable to Na+/K+/Ca2+
reversal potential ~ 0mV
therefore generates fast(-ish) EPSP
• Pharmacology
– agonist = NMDA
– antagonist = AP5
• Molecular biology
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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
Mg2+
+60 mV
Na/K/Ca
2pA
20msec
0 mV
Na/K/Ca
-60 mV
Na/K/Ca
Mg2+
I-V curve
I (pA)
2pA
20msec
V (mV)
-50
Mg2+
Mg2+-free
+50
• Molecular biology
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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
NMDA
+ CM
CM
100pA
10sec
NMDA
glycine
NMDA
NMDA
+ glycine
+ glycine + strychnine
• Molecular biology
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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
• Molecular biology
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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”
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
H2N
COOH
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
• 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
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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