Structure and gating mechanism of the α7 nicotinic acetylcholine receptor

Colleen M. Noviello, Anant Gharpure, Nuriya Mukhtasimova, Rico Cabuco, Leah Baxter, Dominika Borek, Steven M. Sine, Ryan E. Hibbs

Research output: Contribution to journalArticlepeer-review

Abstract

The α7 nicotinic acetylcholine receptor plays critical roles in the central nervous system and in the cholinergic inflammatory pathway. This ligand-gated ion channel assembles as a homopentamer, is exceptionally permeable to Ca2+, and desensitizes faster than any other Cys-loop receptor. The α7 receptor has served as a prototype for the Cys-loop superfamily yet has proven refractory to structural analysis. We present cryo-EM structures of the human α7 nicotinic receptor in a lipidic environment in resting, activated, and desensitized states, illuminating the principal steps in the gating cycle. The structures also reveal elements that contribute to its function, including a C-terminal latch that is permissive for channel opening, and an anionic ring in the extracellular vestibule that contributes to its high conductance and calcium permeability. Comparisons among the α7 structures provide a foundation for mapping the gating cycle and reveal divergence in gating mechanisms in the Cys-loop receptor superfamily.

Original languageEnglish (US)
Pages (from-to)2121-2134.e13
JournalCell
Volume184
Issue number8
DOIs
StatePublished - Apr 15 2021

Keywords

  • acetylcholine receptor
  • cryo-EM
  • Cys-loop receptor
  • ion channel
  • ligand-gated ion channel
  • nicotinic receptor
  • α7

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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