Stoichiometry for α-bungarotoxin block of α7 acetylcholine receptors

Corrie J. B. daCosta (), Chris R. Free and Steven M. Sine ()
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Corrie J. B. daCosta: Mayo Clinic College of Medicine
Chris R. Free: Mayo Clinic College of Medicine
Steven M. Sine: Mayo Clinic College of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9057

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