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Derepression may masquerade as activation in ligand-gated ion channels.

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.

SUBMITTER: Tessier CJG

PROVIDER: S-EPMC10076327 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Derepression may masquerade as activation in ligand-gated ion channels.

Tessier Christian J G CJG Emlaw Johnathon R JR Sturgeon Raymond M RM daCosta Corrie J B CJB

Nature communications 20230405 1

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 reli ...[more]

PMID: 37019877

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