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Updated: Aug 4, 2025

Site Directed Spin Labeling and EPR Spectroscopic Studies of Pentameric Ligand-Gated Ion Channels
Published on: July 4, 2016
Derepression may masquerade as activation in ligand-gated ion channels
Christian J G Tessier1, Johnathon R Emlaw1, Raymond M Sturgeon1
1Department of Chemistry and Biomolecular Sciences, Centre for Chemical and Synthetic Biology, University of Ottawa, Ottawa, ON, Canada.
Abstract:
Agonists are ligands that bind to receptors and activate them. In the case of ligand-gated ion channels, such as the muscle-type nicotinic acetylcholine receptor, mechanisms of agonist activation have been studied for decades. Taking advantage of a reconstructed ancestral muscle-type β-subunit that forms spontaneously activating homopentamers, here we show that incorporation of human muscle-type α-subunits appears to repress spontaneous activity, and furthermore that the presence of agonist relieves this apparent α-subunit-dependent repression. Our results demonstrate that rather than provoking channel activation/opening, agonists may instead 'inhibit the inhibition' of intrinsic spontaneous activity. Thus, agonist activation may be the apparent manifestation of agonist-induced derepression. These results provide insight into intermediate states that precede channel opening and have implications for the interpretation of agonism in ligand-gated ion channels.
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