Modulation of the mammalian GABA 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 receptor. The overall goal of this study was to investigate the modulatory actions of selected α7-PAMs on the GABA 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 receptor by three representative α7-PAMs.

Key Results: We show that the α7-PAMs at micromolar concentrations enhance the apparent affinity of the GABA receptor for the transmitter and potentiate current responses from the receptor. The compounds were equi-effective at binary αβ and ternary αβγ GABA 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 receptor. Given the similarities in the in vitro sensitivities of the α7 nACh and α1β2γ2L GABA receptors to α7-PAMs, we propose that doses used to produce nACh receptor-mediated behavioural effects in vivo are likely to modulate GABA receptor function.