Insights into the biophysical properties of GABAA ion channels: Modulation of ion permeation by drugs and protein interactions

Abstract

The fundamental properties of ion channels assure their selectivity for a particular ion, its rapid permeation through a central pore and that such electrical activity is modulated by factors that control the opening and closing (gating) of the channel. All cell types possess ion channels and their regulated flux of ions across the membrane play critical roles in all steps of life. An ion channel does not act alone to control cell excitability but rather forms part of larger protein complexes. The identification of protein interaction partners of ion channels and their influence on both the fundamental biophysical properties of the channel and its expression in the membrane are revealing the many ways in which electrical activity may be regulated. Highlighted here is the novel use of the patch clamp method to dissect out the influence of protein interactions on the activity of individual GABA(A) receptors. The studies demonstrate that ion conduction is a dynamic property of a channel and that protein interactions in a cytoplasmic domain underlie the channel's ability to alter ion permeation. A structural model describing a reorganisation of the conserved cytoplasmic gondola domain and the influence of drugs on this process are presented.

Agonist-dependent Endocytosis of γ-Aminobutyric Acid Type A (GABAA) Receptors Revealed by a γ2(R43Q) Epilepsy Mutation

“…Moreover, electrophysiological recordings and kinetic analyses have shown that the long distance effects of ␥2(R43Q) substitution extend as far as the transmembrane domains (52). Therefore, ␥2(R43Q) mutation might have an influence on receptor endocytosis in line with the current views on pentameric ligand-gated ion channels, describing a link between extracellular, transmembrane, and intracellular domains (53,65,66).…”

Utrophin regulates modal gating of mechanosensitive ion channels in dystrophic skeletal muscle

“…). GABA A receptor channels show changes in sub‐state gating and single‐channel conductance when clustered rather than when dispersed at low densities, presumably through MA domain interactions between adjacent channels (Tierney, ). MS channels in embryonic stem cells show transitions between three current levels both within single activations and also as isolated events (Soria et al .…”

2′‐Methoxy‐6‐methylflavone: a novel anxiolytic and sedative with subtype selective activating and modulating actions at GABAA receptors

“…These receptors are believed to exist in a 2:2:1 stoichiometry in vivo (McKernan and Whiting, 1996). The subunit composition determines the GABA sensitivity, the pharmacological properties of the GABA A receptor (Olsen and Sieghart, 2009) and the receptor interaction partners mediated by the larger intracellular loop between M3 and M4 (Tierney, 2011).…”