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Derepression may masquerade as activation in ligand-gated ion channels

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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)

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.

Suggested Citation

  • Christian J. G. Tessier & Johnathon R. Emlaw & Raymond M. Sturgeon & Corrie J. B. daCosta, 2023. "Derepression may masquerade as activation in ligand-gated ion channels," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36770-z
    DOI: 10.1038/s41467-023-36770-z
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    References listed on IDEAS

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    1. Remigijus Lape & David Colquhoun & Lucia G. Sivilotti, 2008. "On the nature of partial agonism in the nicotinic receptor superfamily," Nature, Nature, vol. 454(7205), pages 722-727, August.
    2. Craig A. Sexton & Reka Penzinger & Martin Mortensen & Damian P. Bright & Trevor G. Smart, 2021. "Structural determinants and regulation of spontaneous activity in GABAA receptors," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    3. Nuriya Mukhtasimova & Won Yong Lee & Hai-Long Wang & Steven M. Sine, 2009. "Detection and trapping of intermediate states priming nicotinic receptor channel opening," Nature, Nature, vol. 459(7245), pages 451-454, May.
    4. Corrie J. B. daCosta & Chris R. Free & Steven M. Sine, 2015. "Stoichiometry for α-bungarotoxin block of α7 acetylcholine receptors," Nature Communications, Nature, vol. 6(1), pages 1-10, November.
    5. Stephen P. Kelley & James I. Dunlop & Ewen F. Kirkness & Jeremy J. Lambert & John A. Peters, 2003. "A cytoplasmic region determines single-channel conductance in 5-HT3 receptors," Nature, Nature, vol. 424(6946), pages 321-324, July.
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