Extrasynaptic GABAA receptors: Subunit composition, distribution, and regulation

Abstract

Among the multiple GABAA receptor (GABAAR) subtypes that are assembled from the 18 subunits encoded in the mammalian genome, several of them, notably those containing the subunits a4, a5, a6, and d are preferentially located outside of the postsynaptic density and are activated tonically by GABA. Owing to their subunit composition, these extrasynaptic GABAAR have specific functional properties and pharmacological profiles that distinguish them from "postsynaptic" receptors. In this chapter, we summarize anatomical, developmental, and cell biological evidence that extrasynaptic GABAAR represent a specialized subset of GABAAR with specific functional roles and regulation mechanisms. Anatomically, the regional and cellular distribution of the subunits forming extrasynaptic GABAAR explains their enrichment in cerebellum, thalamus, hippocampus, dentate gyrus, striatum, olfactory bulb, and possibly spinal cord. Little is known about the ontogeny of these receptors during central nervous system (CNS) development and neurogenesis, but it is likely that extrasynaptic receptors on progenitor cells and differentiating neurons differ from their adult counterparts, notably owing to late onset of a6 and d subunit expression. On the cell biological level, the extrasynaptic localization of receptors containing the a4, a5, and d subunits depends on structural motifs that either prevent interaction with the postsynaptic scaffolding molecule gephyrin or allow interaction with radixin, a member of the ezrin/radixin/moesin family of actin-interacting proteins. Importantly, there is evidence indicating that regulation of GABAAR trafficking and cell-surface expression, mediated in part by protein phosphorylation mechanisms, allows for rapid changes in the ratio of extrasynaptic/ postsynaptic receptors upon physiological and pathophysiological stimuli. A better understanding of the subcellular localization and regulation of extrasynaptic GABAAR will be required to unravel their multiple contributions to the control of neuronal network activity and behavior.