GABAB Receptors: Physiological Functions and Mechanisms of Diversity

GABAB receptors are the G-protein-coupled receptors (GPCRs) for γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the central nervous system. GABAB receptors are implicated in the etiology of a variety of psychiatric disorders and are considered attractive drug targets. With the cloning of GABAB receptor subunits 13 years ago, substantial progress was made in the understanding of the molecular structure, physiology, and pharmacology of these receptors. However, it remained puzzling that native studies demonstrated a heterogeneity of GABAB responses that contrasted with a very limited diversity of cloned GABAB receptor subunits. Until recently, the only firmly established molecular diversity consisted of two GABAB1 subunit isoforms, GABAB1a and GABAB1b, which assemble with GABAB2 subunits to generate heterodimeric GABAB(1a,2) and GABAB(1b,2) receptors. Using genetic, ultrastructural, biochemical, and electrophysiological approaches, it has been possible to identify functional properties that segregate with these two receptors. Moreover, receptor modifications and factors that can alter the receptor response have been identified. Most importantly, recent data reveal the existence of a family of auxiliary GABAB receptor subunits that assemble as tetramers with the C-terminal domain of GABAB2 subunits and drastically alter pharmacology and kinetics of the receptor response. The data are most consistent with native GABAB receptors minimally forming dimeric assemblies of units composed of GABAB1, GABAB2, and a tetramer of auxiliary subunits. This represents a substantial departure from current structural concepts for GPCRs.