Pharmacology 18a - Principles of GABAergic Transmission

Anil Chopra

  1. Which are the principal inhibitory and excitatory amino acid neurotransmitters in the mammalianCNS? 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]

ii)Extrapyramidal Activity [Basal Ganglia]

iii)Emotional Behaviour [Limbic System]

iv)Endocrine Function [Hypothalamus]

GABA Synthesis

GAD = Glutamate decarboxylase

GABA-T = Gamma-Aminobutyric Acid Transaminase

SSDH = Succinic semialdehyde dehydrogenase


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)andconvulsant.

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).

Antagonised by phaclofen and saclofen.

GABA Inactivation

GABA is taken into the presynaptic neuronal cells as well as into glial cells. This 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.

This occurs in the mitochondria of the pre-synaptic neurones and glial cells.

Both sodium valproate and vigabatrininhibit the metabolism of GABA.