Comparison of αßδ and αßγ GABAA receptors: Allosteric modulation and identification of subunit arrangement by site-selective general anesthetics.

GABAA 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: αßγ receptors mediate phasic inhibition in response to transient high-concentrations of synaptic GABA release, and αßδ receptors produce tonic inhibitory currents activated by low-concentration extrasynaptic GABA. Both αßδ and αßγ 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 αßγ vs. αßδ receptors. Many of these differences are explained by correcting for the high agonist efficacy of GABA at most αßγ receptors vs. much lower efficacy at αßδ receptors. The stoichiometry and subunit arrangement of recombinant αßγ receptors are well established as ß-α-γ-ß-α, while those of αßδ receptors remain controversial. Importantly, some potent general anesthetics selectively bind in transmembrane inter-subunit pockets of αßγ receptors: etomidate acts at ß+/α- interfaces, and the barbiturate R-5-allyl-1-methyl-5-(m-trifluoromethyl-diazirynylphenyl) barbituric acid (R-mTFD-MPAB) acts at α+/ß- and γ+/ß- interfaces. Thus, these drugs are useful as structural probes in αßδ 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 α1ß3δ receptors may share stoichiometry and subunit arrangement with α1ß3γ2 receptors.