GABA_A Receptors

GABA_A Receptor Subunits

The majority of human endogenous GABA_A receptors are composed of α1-, β2- and γ2-subunits in a 2:2:1 ratio (α2β2γ), however the exact subunit conformation is determined by the expression of different subunits in a given cell type. Some subunits are only expressed in specific brain areas, for example receptors containing the α2-subunit are found in regions where the α1-subunit is absent or expressed at low levels, such as the hippocampus and olfactory bulb. Similarly, the α3-subunit is found in the lateral septum and specific nuclei of the brainstem and thalamus, and the α6-subunit is almost exclusively expressed in the cerebellum. GABA_A subunit conformation can also be different at different locations on the same neuron, a process that is mediated by membrane anchoring proteins.

GABA_A Receptor Pharmacology

As a results of the heterogeneity of GABA_A receptor subunits, and also the presence of multiple binding sites for different compound classes, the pharmacological properties of individual GABA_A receptors are very complex. In general, ligands that contribute to or potentiate receptor activation have anticonvulsant, sedative, hypnotic and muscle relaxant effects. In contrast, ligands that decrease receptor activation have the opposite effect; they are convulsant and anxiogenic and may also have nootropic effects.

Depending on the subunit conformation of a GABA_A receptor all or a selection of the following pharmacological binding sites may be present.

The GABA binding site of GABA_A receptors is located at the interface of α- and β-subunits. The specific α- and β-subunit subtypes in a receptor modulate the efficacy of GABA and competitive ligands at this binding site.

The benzodiazepine binding site is located at the interface of α- and γ-subunits and as such, GABA_A receptors that lack a γ-subunit are insensitive to benzodiazepines. Binding of benzodiazepines to this site potentiates GABAergic transmission by locking the receptor into a state that increases its affinity for GABA. This potentiates the inhibitory effect of GABA binding by increasing the frequency of channel opening and therefore hyperpolarization of the synaptic membrane. Some benzodiazepines show selectivity for specific α-subunits and have differing pharmacological profiles. For example, α1- and α5-subunit selective benzodiazepines are associated with sedation and amnesia, whereas α2- and α3-subunit selective benzodiazepines, such as TCS 1105 (Cat. No. 3942) are associated with anxiolytic effects. α4- and α6 subunits generally have a low affinity for classical benzodiazepines, particularly in the presence of a δ-subunit.

The picrotoxin binding site of GABA_A receptors is location within the ion pore. Compounds that bind here, such as picrotoxin (Cat. No. 1128) have an antagonistic effect on GABAergic transmission as they physically occlude the ion pore and prevent the passage of Cl^- into the cell. They are often described as non-competitive channel blockers.

There are also multiple other allosteric ligand binding sites on GABA_A receptors, where ligands that bind have a modulatory effect on GABAergic transmission. For example, ethanol binds with high affinity to δ-subunits and with low affinity to an allosteric transmembrane binding site on α-subunits. Similarly, neurosteroids such as THDOC (Cat. No. 6334) promote channel opening of GABA_A receptors that contain the δ-subunit. Barbiturates, such as primidone (Cat. No. 0830), also bind to multiple allosteric transmembrane binding sites, and binding increases the duration of ion channel opening in response to GABA binding. The actions of benzodiazepines, barbiturates and ethanol at GABA_A receptors is synergistic, resulting in a high chance of overdose if drug interactions are not carefully controlled.

External sources of pharmacological information for GABA_A Receptors :

• IUPHAR Receptor Code

• BJP Guide

Literature for GABA_A Receptors

Tocris offers the following scientific literature for GABA_A Receptors to showcase our products. We invite you to request* your copy today!

*Please note that Tocris will only send literature to established scientific business / institute addresses.

GABA Receptors Scientific Review

Written by Ian Martin, Norman Bowery and Susan Dunn, this review provides a history of the GABA receptor, as well as discussing the structure and function of the various subtypes and the clinical potential of receptor modulators; compounds available from Tocris are listed.

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Addiction Poster

The key feature of drug addiction is the inability to stop using a drug despite clear evidence of harm. This poster describes the brain circuits associated with addiction, and provides an overview of the main classes of addictive drugs and the neurotransmitter systems that they target.

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GABA_A Receptor Gene Data