Heterogeneity of GABAA Receptors: Revived Interest in the Development of Subtype-selective Drugs

W.      Sieghart; M.      Ernst

doi:10.2174/1568015054863837

Abstract

Gamma-aminobutyric acid (GABA) is the most important inhibitory transmitter in the central nervous system. Most of the actions of GABA are mediated by GABAA receptors. These are choride ion channels that can be opened by GABA and can be modulated by a variety of pharmacologically and clinically important drugs. GABAA receptors are composed of five subunits that can belong to different subunit classes. So far, 19 different subunits have been identified in mammalian brain, exhibiting a distinct but overlapping regional and cellular distribution and giving rise to an enormous heterogeneity of GABAA receptors. Depending on the subunit composition these receptors exhibit distinct electrophysiological and pharmacological properties. Drugs in clinical use are only weakly receptor subtype selective, explaining their similar and broad pharmacological effects. Investigations of mice with a point mutation in a GABAA receptor subunit that eliminates the actions of drugs on certain receptors, only, have indicated that different receptor subtypes mediate distinct actions of GABAergic drugs. This conclusion was supported by experiments with newly developed compounds exhibiting a significantly increased receptor subtype selectivity, suggesting a tremendous clinical potential of drugs with high selectivity for certain receptor subtypes. In addition, the recent availability of structural information on GABAA receptors from homology modeling studies will stimulate experiments leading to the identification of the binding sites of the various GABAA receptor ligands. Accumulating structural information on receptor subtypes will finally lead to more precise pharmacophore models that will provide the basis for a more rational drug design.

Keywords: gabaa receptors, subtypes, subunits, structure, distribution, function, pharmacology

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