GABA receptor

The GABA receptors are a class of receptors that respond to the neurotransmitter γ-aminobutyric acid (GABA), the chief inhibitory neurotransmitter in the vertebrate central nervous system. There are three classes of GABA receptors: GABAA, GABAB, and GABAС.

GABAA and GABAС receptors are ligand-gated ion channels (also known as ionotropic receptors), whereas GABAB receptors are G protein-coupled receptors (also known as metabotropic receptors).

GABAA
It has long been recognized that the fast response of neurons to GABA that is blocked by bicuculline and picrotoxin is due to direct activation of an anion channel.

This channel was subsequently termed the GABAA receptor. Fast-responding GABA receptors are members of family of Cys-loop ligand-gated ion channels. Members of this superfamily, which includes nicotinic acetylcholine receptors, GABAA and GABAС receptors, glycine and 5-HT3 receptors, possess a characteristic loop formed by a disulphide bond between two cysteine residues.

GABAС
A second type of ionotropic GABA receptors, insensitive to typical allosteric modulators of GABAA receptor channels such as benzodiazepines and barbiturates,  was designated GABAС receptor.

Native responses of the GABAС receptor type occur in retinal bipolar or horizontal cells across vertebrate species. GABAС receptors are exclusively composed of ρ subunits that are related to GABAA receptor subunits.

Although the term "GABAС receptor" is frequently used, GABAС may be viewed as a variant within the GABAA receptor family. However others have argued that the differences between GABAС and GABAA receptors are large enough to justify maintaining the distinction between these two subclasses of GABA receptors.

Common characteristics
In ionotropic GABAA and GABAС receptors, binding of GABA molecules to their binding sites in the extracellular part of receptor triggers opening of a chloride ion-selective pore.

Opening of a chloride conductance drives the membrane potential towards the reversal potential of the Cl¯ ion which is about –80 mV in neurons, inhibiting the firing of new action potentials.

However, there are numerous reports on GABAA receptors, which are actually excitatory. This phenomenon is due to increased intracellular concentration of Cl¯ ions either during development of the nervous system or in certain cell populations.

After this period of development, a Chloride pump is upregulated and inserted into the cell membrane, pumping Cl- ions into the extracellular space of the cell. Further openings via GABA binding to the receptor then produce inhibitory responses. Over-excitation of this receptor induces receptor remodeling and the eventual invagination of the GABA receptor. As a result, further GABA binding becomes inhibited and IPSPs are no longer relevant.

G protein coupled receptor: GABAB
A slow response to GABA is mediated by GABAB receptors, originally defined on the basis of pharmacological properties.

In studies focused on the control of neurotransmitter release, it was noted that a GABA receptor was responsible for modulating evoked release in a variety of isolated tissue preparations. This ability of GABA to inhibit neurotransmitter release from these preparations was not blocked by bicuculline, was not mimicked by isoguvacine, and was not dependent on Cl¯, all of which are characteristic of the GABAA receptor. The most striking discovery was the finding that baclofen (β-parachlorophenyl GABA), a clinically employed spasmolytic mimicked, in a stereoselective manner, the effect of GABA.

Later ligand-binding studies provided direct evidence of binding sites for baclofen on central neuronal membranes. cDNA cloning confirmed that the GABAB receptor belongs to the family of G-protein coupled receptors. Additional information on GABAB receptors has been reviewed elsewhere.

Summary
Thus, GABAA and GABAС receptors are ligand-gated ion channels, whereas GABAB receptors are G protein-coupled receptors.

This has a parallel to several other systems in the body, where a single molecule binds to receptors which function in completely different ways:


 * acetylcholine binds to nicotinic and muscarinic receptors
 * serotonin binds to 5-HT3 and metabotropic receptors
 * glutamate binds to ionotropic and metabotropic receptors
 * purines bind to ionotropic nucleotide-gated P2X and G protein-coupled P2Y receptors