GABA receptor

Gamma-aminobutyric acid

The GABA receptors are a class of receptors that respond to the neurotransmitter gamma-aminobutyric acid (GABA), the chief inhibitory in the mature vertebrate central nervous system. There are two classes of GABA receptors: GABA_A and GABA_B.

GABA_A receptors are ligand-gated ion channels (also known as ionotropic receptors), whereas GABA_B receptors are G protein-coupled receptors (also known as metabotropic receptors).

Ligand-gated ion channels: GABA_A

Cell GABA receptor.

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 GABA_A 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, GABA_A receptors, glycine and 5-HT₃ receptors, possess a characteristic loop formed by a disulfide bond between two cysteine residues.

In ionotropic GABA_A receptors, binding of GABA molecules to their binding sites in the extracellular part of the receptor triggers opening of a chloride ion-selective pore. The increased chloride conductance drives the membrane potential towards the reversal potential of the Cl¯ ion which is about –65 mV in neurons, inhibiting the firing of new action potentials. This mechanism is responsible for the sedative effects of GABA_A allosteric agonists.

However, there are numerous reports of excitatory GABA_A receptors. 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 tissue. 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.

GABA_A-ρ subclass (formerly GABA_C)

Main article: GABAA-rho receptor

A subclass of ionotropic GABA receptors, insensitive to typical allosteric modulators of GABA_A receptor channels such as benzodiazepines and barbiturates, was designated GABA_С receptor. Native responses of the GABA_C receptor type occur in retinal bipolar or horizontal cells across vertebrate species.

GABA_С receptors are exclusively composed of ρ (rho) subunits that are related to GABA_A receptor subunits. Although the term "GABA_С receptor" is frequently used, GABA_С may be viewed as a variant within the GABA_A receptor family. Others have argued that the differences between GABA_С and GABA_A receptors are large enough to justify maintaining the distinction between these two subclasses of GABA receptors. However, since GABA_С receptors are closely related in sequence, structure, and function to GABA_A receptors and since other GABA_A receptors besides those containing ρ subunits appear to exhibit GABA_С pharmacology, the Nomenclature Committee of the IUPHAR has recommended that the GABA_С term no longer be used and these ρ receptors should be designated as the ρ subfamily of the GABA_A receptors (GABA_A-ρ).

G protein coupled receptor: GABA_B

Main article: GABAB receptor

A slow response to GABA is mediated by GABA_B 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 GABA_A 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 GABA_B receptor belongs to the family of G-protein coupled receptors. Additional information on GABA_B receptors has been reviewed elsewhere.

Other receptors

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

• acetylcholine binds to nicotinic and muscarinic acetylcholine 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

See also

• Dopamine receptor
• GABA agonist
• GABA antagonist

External links

• IUPHAR GPCR Database - GABA_B receptors
• GABA Receptor at the US National Library of Medicine Medical Subject Headings (MeSH)