Importance of a novel GABA_A receptor subunit for benzodiazepine pharmacology

Abstract

NEUROTRANSMISSION effected by GABA (γ-aminobutyric acid) is predominantly mediated by a gated chloride channel intrinsic to the GABA_A receptor. This heterooligomeric receptor¹ exists in most inhibitory synapses in the vertebrate central nervous system (CNS) and can be regulated by clinically important compounds such as benzodiazepines and barbiturates². The primary structures of GABA_A receptor α- and β-subunits have been deduced from cloned complementary DNAs^3,4. Co-expression of these subunits in heterologous systems generates receptors which display much of the pharmacology of their neural counterparts, including potentiation by barbiturates^3–5. Conspicuously, however, they lack binding sites for, and consistent electrophysiological responses to, benzodiazepines^4,5. We now report the isolation of a cloned cDNA encoding a new GABA_A receptor subunit, termed γ2, which shares approximately 40% sequence identity with α-and β-subunits and whose messenger RNA is prominently localized in neuronal subpopulations throughout the CNS. Importantly, coexpression of the γ2 subunit with α1 and β1 subunits produces GABA_A receptors displaying high-affinity binding for central benzodiazepine receptor ligands.