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Nat Commun. 2015 Aug 18;6:8057. doi: 10.1038/ncomms9057.

Stoichiometry for α-bungarotoxin block of α7 acetylcholine receptors.

Author information

1
Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905, USA.
2
1] Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905, USA [2] Department of Neurology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, Minnesota 55905, USA.

Abstract

α-Bungarotoxin (α-Btx) binds to the five agonist binding sites on the homopentameric α7-acetylcholine receptor, yet the number of bound α-Btx molecules required to prevent agonist-induced channel opening remains unknown. To determine the stoichiometry for α-Btx blockade, we generate receptors comprised of wild-type and α-Btx-resistant subunits, tag one of the subunit types with conductance mutations to report subunit stoichiometry, and following incubation with α-Btx, monitor opening of individual receptor channels with defined subunit stoichiometry. We find that a single α-Btx-sensitive subunit confers nearly maximal suppression of channel opening, despite four binding sites remaining unoccupied by α-Btx and accessible to the agonist. Given structural evidence that α-Btx locks the agonist binding site in an inactive conformation, we conclude that the dominant mechanism of antagonism is non-competitive, originating from conformational arrest of the binding sites, and that the five α7 subunits are interdependent and maintain conformational symmetry in the open channel state.

PMID:
26282895
PMCID:
PMC4544739
DOI:
10.1038/ncomms9057
[Indexed for MEDLINE]
Free PMC Article

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