GABA-A receptors: pharmacology, behavioral roles, and motor disorders

τ-Aminobutyric acid (GABA), the most prevalent inhibitory neurotransmitter in the mammalian brain, exerts its main action through GABAA receptors. They belong to the superfamily of ligand-gated ion channels and respond to GABA by the opening of an intrinsic anion channel. Multiple GABAA receptor subtypes in the brain show differential regional and developmental expression patterns. The receptors have a pentameric structure and are formed from members of at least three different subunit families (α1–6, β1–3, and τ1–3). The regulation of functional properties by GABA and its analogs and by benzodiazepine (BZ) receptor ligands differs dramatically with the type of α variant in the receptor complex. Additional variations of GABAA receptors result from substitution of γ subunits. The role of the β subunits, which are essential for receptor assembly, is less well defined on a functional basis. Besides their involvement in anxiolysis and sedation, GABAA receptors clearly have an impact on motor coordination. However, with the possible exception of the alcohol-and BZ-sensitive alcohol non-tolerant (ANT) rat line, it is not well documented whether a genetic alteration in this receptor system is directly involved in the impairment of animal or human motor activity.</jats:p

Modulation of GABA-A receptor tert-[35S]butylbicyclophosphorothionate binding by antagonists: relationship to patterns of subunit expression

The multisubunit gamma−aminobutyric acid type A (GABA<SUB>A</SUB>) receptor is heterogeneous in molecular and pharmacological aspects. We used quantitative autoradiographic techniques to generate detailed pharmacological profiles for the binding of the GABA<SUB>A</SUB>−receptor ionophore ligand tert−[<SUP>35</SUP>S]butylbicyclophosphorothionate ([<SUP>35</SUP>S]TBPS) and its modulation by GABA and the GABA<SUB>A</SUB> antagonists bicuculline and 2−(3−carboxy−2,3−propyl)−3−amino−6−p−methoxyphenylpyrazinium bromide (SR 95531). Regional differences in the actions of bicuculline and SR 95531 were correlated with the expression of 13 GABA<SUB>A</SUB> subunits in brain as reported previously. In some brain regions SR 95531 reduced [<SUP>35</SUP>S]TBPS binding much more than bicuculline, as illustrated by high ratios of bicuculline− to SR 95531−modulated [<SUP>35</SUP>S]TBPS binding. This ratio correlated positively with alpha2−subunit mRNA levels. Binding that was equally affected by SR 95531 and bicuculline occurred prominently in regions with abundant alpha1 mRNA expression. The present findings thus reveal a novel pharmacological heterogeneity based on differences between alpha1 and alpha2 subunit−containing GABA<SUB>A</SUB> receptors. The data aid in developing GABA<SUB>A</SUB>−receptor subtype−specific antagonists and in establishing receptor domains critical for the actions of GABA<SUB>A</SUB> antagonist