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

• Published in: bioRxiv
• Main Authors: Tessier, Christian Jg, Emlaw, Johnathon R, Sturgeon, Raymond M, Dacosta, Corrie Jb
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 15.09.2022
• Subjects: Agonists; Channel opening; Derepression; Ion channels; Ion channels (ligand-gated)
• DOI: 10.1101/2022.09.13.507804

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 represses spontaneous activity, and furthermore that the presence of agonist relieves this 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. Competing Interest Statement The authors have declared no competing interest.