Derepression may masquerade as activation in ligand-gated ion channels

Christian J. G. Tessier, Johnathon R. Emlaw, Raymond M. Sturgeon and Corrie J. B. daCosta ()
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Christian J. G. Tessier: Centre for Chemical and Synthetic Biology, University of Ottawa
Johnathon R. Emlaw: Centre for Chemical and Synthetic Biology, University of Ottawa
Raymond M. Sturgeon: Centre for Chemical and Synthetic Biology, University of Ottawa
Corrie J. B. daCosta: Centre for Chemical and Synthetic Biology, University of Ottawa

Nature Communications, 2023, vol. 14, issue 1, 1-8

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36770-z

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