Download Pharmacology 18a – Priciples of GABAergic Transmission

Pharmacology 18a - Principles of GABAergic Transmission
Anil Chopra
1. Which are the principal inhibitory and excitatory amino acid neurotransmitters in
the mammalian CNS? With which types of neurons are these transmitters
associated?
2. Briefly describe the processes involved in GABAergic synaptic transmission.
How may this knowledge be useful in the design of novel therapeutically useful
drugs?
3. Compare and contrast the principal characteristics of GABA-A and GABA-B
receptors
There are a number of different types of neurotransmitter in the CNS:
Inhibitory (neutral amino acids)
 GABA (γ-AMINOBUTYRIC ACID)
 GLYCINE
Excitatory (acidic amino acids)
 GLUTAMATE
 ASPARTATE
 (L-HOMOCYSTEATE?)
GABA
GABA is mainly found in the central nervous system in the cortex, cerebellum,
hippocampus, corpus striatum, and hypothalamus and in the dorsal horn of the spinal
cord. GABA neurones are generally short intermediate inhibitory neurones which
therefore have a widespread inhibitory action. It has a number of different functions:
i) Motor Activity [Cortex, Cerebellum, Cord]
GABA SYNTHESIS
ii) Extrapyramidal Activity [Basal Ganglia]
GABA ‘shunt’
iii) Emotional Behaviour [Limbic System]
iv) Endocrine Function [Hypothalamus]
GAD
GABA Synthesis
GABA
GAD = Glutamate decarboxylase
GABA-T = Gamma-Aminobutyric Acid Transaminase
SSDH = Succinic semialdehyde
Succinic
semialdehyde
dehydrogenase
Transaminase
GABA-T
Glycine
-Oxoglutarate
Succinate
SSDH
Aspartate
Glyoxylate
Glutamate
KREBS CYCLE
Oxaloacetate
Transaminase
Inhibitory amino acids
Excitatory amino acids
Oxaloacetate
α-oxoglutarate
Krebs Cycle
Glutamate
GABA
GABA-T
GAD
GABA Transaminase
GABA Decarboxylase
GABA Storage and Release
GABA is stored in vesicles in nerve terminals (like any other neurotransmitter) and is
released by exocytosis upon influx of calcium ions.
GABA Receptors
There are 2 types of GABA receptor:
GABAA
 Generally POSTsynaptic
 When activated by GABA cause influx of Cl- ions
 This causes the cell to hyperpolarise which will decrease the likelihood of it
firing an action potential.
 Agonised by muscimol (+ GABA)
 Antagonised by bicuculline (competitive), picrotoxin (non-competitive) and
convulsant.
GABAB
 Generally PREsynaptic
 Inhibit the release of neurotransmitter
 They are autoreceptors that inhibit GABA release
 Heterocpetors e.g. reduce dopamine release at dopaminergic synapses.
 The are G-protein linked and hence use cAMP as a second messenger.
 They cause a decrease in Ca2+ conductance and an increase in K+ conductance.
 Agonised by baclofen (often used as muscle relaxant).
Oxaloacetate
α-oxoglutarate
Glutamate
GABA
 Antagonised by phaclofen
and saclofen.
GABA Inactivation
Krebs Cycle
GABA-T
GAD
GABA is taken into the presynaptic neuronal
cells as well as into
glial
cells. This
GABA Transaminase
GABA
Decarboxylase
process is Na+ - dependent, energy dependent and saturable.
GABA Metabolism
GABA is converted into Succinic semialdehyde by GABA Transaminase and then
the succinic semialdehyde is converted to succinic acid by succinic semialdehyde
dehydrogenase.
Succinic
Semi-aldehyde
GABA
Succinic Acid
GABA-T
SSDH
GABA Transaminase
Succinate Semialdehyde
Dehydrogenase
This occurs in the mitochondria of the pre-synaptic neurones and glial cells.
Both sodium valproate and vigabatrin inhibit the metabolism of GABA.
Krebs
Cycle