Comparison of αβδ and αβγ GABAA receptors: Allosteric modulation and identification of subunit arrangement by site-selective general anesthetics

GABA(A) receptors play a dominant role in mediating inhibition in the mature mammalian brain, and defects of GABAergic neurotransmission contribute to the pathogenesis of a variety of neurological and psychiatric disorders. Two types of GABAergic inhibition have been described: alpha beta gamma receptors mediate phasic inhibition in response to transient high-concentrations of synaptic GABA release, and alpha beta delta receptors produce tonic inhibitory currents activated by low-concentration extrasynaptic GABA. Both alpha beta delta and alpha beta gamma receptors are important targets for general anesthetics, which induce apparently different changes both in GABA-dependent receptor activation and in desensitization in currents mediated by alpha beta gamma vs. alpha beta delta receptors. Many of these differences are explained by correcting for the high agonist efficacy of GABA at most alpha beta gamma receptors vs. much lower efficacy at alpha beta delta receptors. The stoichiometry and subunit arrangement of recombinant alpha beta gamma receptors are well established as beta-alpha-gamma-beta-alpha, while those of 48 receptors remain controversial. Importantly, some potent general anesthetics selectively bind in transmembrane inter-subunit pockets of alpha beta gamma receptors: etomidate acts at beta(+)/alpha(-) interfaces, and the barbiturate R-5-allyl-1-methyl-5-(m-trifluoromethyl-diazirynylphenyl) barbituric acid (R-mTFD-MPAB) acts at alpha(+)/beta(-) and gamma(+)/beta(-) interfaces. Thus, these drugs are useful as structural probes in alpha beta delta receptors formed from free subunits or concatenated subunit assemblies designed to constrain subunit arrangement. Although a definite conclusion cannot be drawn, studies using etomidate and R-mTFD-MPAB support the idea that recombinant alpha 1 beta 3 delta receptors may share stoichiometry and subunit arrangement with alpha 1 beta 3 gamma 2 receptors. (C) 2017 Elsevier Ltd. All rights reserved.