An intersubunit trigger of channel gating in the muscle nicotinic receptor

Nuriya Mukhtasimova, Steven M. Sine

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Binding of neurotransmitter triggers gating of synaptic receptor channels, but our understanding of the structures that link the binding site to the channel is just beginning to develop. Here, we identify an intersubunit triggering element required for rapid and efficient gating of muscle nicotinic receptors using a structural model of the Torpedo receptor at 4 Å resolution, recordings of currents through single receptor channels, measurements of inter-residue energetic coupling, and functional consequences of disulfide trapping. Mutation of the conserved residues, αTyr 127, εAsn 39, and δAsn 41, located at the two subunit interfaces that form the agonist binding sites, markedly attenuates acetylcholine-elicited channel gating; mutant cycle analyses based on changes in the channel gating equilibrium constant reveal strong energetic coupling among these residues. After each residue is substituted with Cys, oxidizing conditions that promote disulfide bond formation attenuate gating of mutant, but not wild-type receptors. Gating is similarly attenuated when the Cys substitutions are confined to either of the binding-site interfaces, but can be restored by reducing conditions that promote disulfide bond breakage. Thus, the Tyr-Asn pair is an intersubunit trigger of rapid and efficient gating of muscle nicotinic receptors.

Original languageEnglish (US)
Pages (from-to)4110-4119
Number of pages10
JournalJournal of Neuroscience
Volume27
Issue number15
DOIs
StatePublished - Apr 11 2007

Keywords

  • Acetylcholine receptor
  • Binding
  • Channel gating
  • Coupling energy
  • Intersubunit trigger
  • Single channel kinetics

ASJC Scopus subject areas

  • Neuroscience(all)

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