Modulation of the mammalian GABA_A receptor by type I and type II positive allosteric modulators of the α7 nicotinic acetylcholine receptor

Background and purpose: Positive allosteric modulators of the α7 nicotinic acetylcholine (nACh) receptor (α7-PAMs) possess promnesic and procognitive properties and have potential in the treatment of cognitive and psychiatric disorders including Alzheimer's disease and schizophrenia. Behavioural studies in rodents have indicated that α7-PAMs can also produce antinociceptive and anxiolytic effects that may be associated with positive modulation of the GABA_A receptor. The overall goal of this study was to investigate the modulatory actions of selected α7-PAMs on the GABA_A receptor.

Experimental approach: We employed a combination of cell fluorescence imaging, electrophysiology, functional competition and site-directed mutagenesis to investigate the functional and structural mechanisms of modulation of the GABA_A receptor by three representative α7-PAMs.

Key results: We show that the α7-PAMs at micromolar concentrations enhance the apparent affinity of the GABA_A receptor for the transmitter and potentiate current responses from the receptor. The compounds were equi-effective at binary αβ and ternary αβγ GABA_A receptors. Functional competition and site-directed mutagenesis indicate that the α7-PAMs bind to the classic anaesthetic binding sites in the transmembrane region in the intersubunit interfaces, which results in stabilization of the active state of the receptor.

Conclusion and implications: We conclude that the tested α7-PAMs are micromolar-affinity, intermediate- to low-efficacy allosteric potentiators of the mammalian αβγ GABA_A receptor. Given the similarities in the in vitro sensitivities of the α7 nACh and α1β2γ2L GABA_A receptors to α7-PAMs, we propose that doses used to produce nACh receptor-mediated behavioural effects in vivo are likely to modulate GABA_A receptor function.