GABA(A) receptors: structure and function in the basal ganglia

Abstract

gamma-Aminobutyric acid type A (GABA(A)) receptors, the major inhibitory neurotransmitter receptors responsible for fast inhibition in the basal ganglia, belong to the superfamily of "cys-cys loop" ligand-gated ion channels. GABA(A) receptors form as pentameric assemblies of subunits, with a central Cl(-) permeable pore. On binding of two GABA molecules to the extracellular receptor domain, a conformational change is induced in the oligomer and Cl(-), in most adult neurons, moves into the cell leading to an inhibitory hyperpolarization. Nineteen mammalian subunit genes have been identified, each showing distinct regional and cell-type-specific expression. The combinatorial assembly of the subunits generates considerable functional diversity. Here we place the focus on GABA(A) receptor expression in the basal ganglia: striatum, globus pallidus, substantia nigra and subthalamic nucleus, where, in addition to the standard alpha1beta2/3gamma2 receptor subtype, significant levels of other subunits (alpha2, alpha3, alpha4, gamma1, gamma3 and delta) are expressed in some nuclei.

Fig. 1

Predicted topology of a GABA_A receptor subunit. The cysteine-disulfide bridge in the N-terminus is indicated by a black bar. Transmembrane domains are shown as open boxes labelled TM1-4.

Fig. 2

Model of the extracellular domains of a pentameric GABA_A receptor consisting of two α, two β and one γ2 subunit. (a) View from the extracellular space. GABA binds to the interface between the α and the β subunit, benzodiazepines bind to the interface between the α and the γ2 subunit. (b) Predicted benzodiazepine-binding pocket between the α and the γ2 subunit, viewed from the side. The binding site loops are labelled A to G. (c) and (d) The α and β subunit viewed from the side. Loops A, B, C, D and E form the predicted GABA-binding pocket (blue volume in (d)). The volume shown in green might be used in antagonist-bound states. (Adapted from Ernst et al., 2003 used with permission.)

Fig. 3

Phasic and tonic GABAergic inhibition. Fast synaptic (phasic) inhibition is mediated mainly via γ2 subunit-containing receptors (shown in black). δ subunit-containing receptors (shown in grey) are located peri- or extrasynaptically and are tonically activated by GABA diffusing out of the synaptic cleft.