Molecular Structure and Physiological Functions of GABABReceptors

Abstract

GABABreceptors are broadly expressed in the nervous system and have been implicated in a wide variety of neurological and psychiatric disorders. The cloning of the first GABABreceptor cDNAs in 1997 revived interest in these receptors and their potential as therapeutic targets. With the availability of molecular tools, rapid progress was made in our understanding of the GABABsystem. This led to the surprising discovery that GABABreceptors need to assemble from distinct subunits to function and provided exciting new insights into the structure of G protein-coupled receptors (GPCRs) in general. As a consequence of this discovery, it is now widely accepted that GPCRs can exist as heterodimers. The cloning of GABABreceptors allowed some important questions in the field to be answered. It is now clear that molecular studies do not support the existence of pharmacologically distinct GABABreceptors, as predicted by work on native receptors. Advances were also made in clarifying the relationship between GABABreceptors and the receptors for γ-hydroxybutyrate, an emerging drug of abuse. There are now the first indications linking GABABreceptor polymorphisms to epilepsy. Significantly, the cloning of GABABreceptors enabled identification of the first allosteric GABABreceptor compounds, which is expected to broaden the spectrum of therapeutic applications. Here we review current concepts on the molecular composition and function of GABABreceptors and discuss ongoing drug-discovery efforts.