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bioRxiv · 10.1101/2022.09.13.507804

Derepression masquerades as activation in a pentameric ligand-gated ion channel

Tessier, C. J. G.·Emlaw, J. R.·Sturgeon, R. M.·daCosta, C. J. B.
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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 {beta}-subunit that forms spontaneously activating homopentamers, here we show that incorporation of human muscle-type -subunits represses spontaneous activity, and furthermore that the presence of agonist relieves this -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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Tessier, C. J. G., Emlaw, J. R., Sturgeon, R. M., daCosta, C. J. B.. 2022-09-15. Derepression masquerades as activation in a pentameric ligand-gated ion channel. https://doi.org/10.1101/2022.09.13.507804

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