Mechanisms of inhibition and activation of extrasynaptic alpha beta GABA(A) receptors

Type A GABA (gamma-aminobutyric acid) receptors represent a diverse population in the mammalian brain, forming pentamers from combinations of alpha-,beta-, gamma-, delta-, epsilon-, rho-, theta- and pi-subunits(1). alpha beta, alpha 4 beta delta, alpha 6 beta delta and alpha 5 beta gamma receptors favour extrasynaptic localization, and mediate an essential persistent (tonic) inhibitory conductance in many regions of the mammalian brain(1,2). Mutations of these receptors in humans are linked to epilepsy and insomnia'. Altered extrasynaptic receptor function is implicated in insomnia, stroke and Angelman and Fragile X syndromes(1,5), and drugs targeting these receptors are used to treat postpartum depression(6). Tonic GABAergic responses are moderated to avoid excessive suppression of neuronal communication, and can exhibit high sensitivity to Zn2+ blockade, in contrast to synapse-preferring alpha 1 beta gamma, alpha 2 beta gamma and alpha 3 beta gamma receptor responses(5,7-12). Here, to resolve these distinctive features, we determined structures of the predominantly extrasynaptic alpha beta GABA(A) receptor class. An inhibited state bound by both the lethal paralysing agent alpha-cobratoxin(13) and Zn2+ was used in comparisons with GABA-Zn2+ and GABA-bound structures. Zn2+ nullifles the GABA response by non-competitively plugging the extracellular end of the pore to block chloride conductance. In the absence of Zn2+, the GABA signalling response initially follows the canonical route until it reaches the pore. In contrast to synaptic GABA(A) receptors, expansion of the midway pore activation gate is limited and it remains closed, reflecting the intrinsic low efficacy that characterizes the extrasynaptic receptor. Overall, this study explains distinct traits adopted by alpha beta receptors that adapt them to a role in tonic signalling.