Structure and gating mechanism of the α7 nicotinic acetylcholine receptor

The alpha 7 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 alpha 7 receptor has served as a prototype for the Cys-loop super family yet has proven refractory to structural analysis. We present cryo-EM structures of the human alpha 7 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 alpha 7 structures provide a foundation for mapping the gating cycle and reveal divergence in gating mechanisms in the Cys-loop receptor superfamily.

Automated summary

The alpha 7 nicotinic acetylcholine receptor plays critical roles in the central nervous system and the cholinergic inflammatory pathway as a ligand-gated ion channel. Recent cryo-EM structures of the human alpha 7 nicotinic receptor in different states have provided insights into its gating cycle and functional elements, including a C-terminal latch and an anionic ring that contribute to its high conductance and calcium permeability. Comparisons among the alpha 7 structures have revealed divergence in gating mechanisms within the Cys-loop receptor superfamily.