GABAA receptor subtypes: structural variety raises hope for new therapy concepts

Abstract

GABAA receptors are ligand-gated chloride ion channels composed of five subunits that can be opened by GABA, and modulated by multiple drugs, some of utmost clinical importance. GABAA receptors occur in the nervous system as well as in peripheral tissues where their function is largely unknown. The existence of multiple GABAA receptor subtypes with distinct subunit composition leads to multiple homologous binding sites with different degrees of similarity. Crystal structures of proteins homologous to GABAA receptors and of a GABAA receptor subtype, combined with homology modeling studies, have provided insights into the possible location of drug interaction sites. Some of these sites have been confirmed by experimental studies. For many receptor ligands, however, binding sites are not yet known. Here we will briefly review the function of distinct types of GABAA receptors and provide structural insights and experimental evidence on binding sites for ligands that could be of considerable clinical interest.