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

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.

Antidepressant effects of an inverse agonist selective for α5 GABA-A receptors in the rat forced swim test

“…Recent genetic studies with mice carrying a point mutation in α1, α2, α3 or α5 subunits have suggested a specifi c contribution of individual receptor subtypes to the spectrum of behavioral actions of these compounds [6]. These genetic advances have encouraged the synthesis and testing of new, selective BZ site ligands, that possess stronger affi nity and/or effi cacy profi les [7]. Here, we focus on α5-containing GABA-A receptors, as these receptors are highly expressed in brain regions substantially involved in memory formation and emotion [8][9][10].…”

PWZ-029, a compound with moderate inverse agonist functional selectivity at GABAA receptors containing α5 subunits, improves passive, but not active, avoidance learning in rats

“…The recent genetic studies with mice carrying a point mutation of histidine to arginine in α 1 , α 2 , α 3 or α 5 subunits, rendering the respective GABA A receptors selectively insensitive to effects of BZ site ligands, suggested a specific contribution of individual receptor subtypes to the spectrum of behavioral actions of these compounds . These genetic advances have encouraged synthesis of new, selective BZ site ligands, that possess affinity and/or efficacy profiles which enable separation of wanted from unwanted effects (Sieghart and Ernst, 2005).…”

Molecular and synaptic organization of GABAA receptors in the cerebellum: Effects of targeted subunit gene deletions

“…GABA A receptors belong to the superfamily of ligand-gated ion channels, along with nicotinic acetylcholine receptors, glycine receptors and 5-HT 3 receptors (1). They form heteropentameric chloride channels gated by GABA and modulated by several clinically relevant drugs, including benzodiazepines, barbiturates, neurosteroids, and ethanol (2)(3)(4). They are assembled for a large family of subunits (a1-6, b1-3, c1-3, d, e, p, and h in mammalian brain), of which 13 are expressed in the cerebellum (5).…”