Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Receptor Biology Laboratory, Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55902, USA.
Cell. 2021 Apr 15;184(8):2121-2134.e13. doi: 10.1016/j.cell.2021.02.049. Epub 2021 Mar 17.
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 Ca, 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.
α7 型烟碱型乙酰胆碱受体在中枢神经系统和胆碱能炎症途径中发挥着关键作用。这种配体门控离子通道以同源五聚体的形式组装，对 Ca 的通透性极高，并且失敏速度比任何其他 Cys 环受体都快。α7 受体一直是 Cys 环超家族的原型，但事实证明它难以进行结构分析。我们展示了在脂质环境中处于静息、激活和脱敏状态的人 α7 型烟碱型乙酰胆碱受体的冷冻电镜结构，阐明了门控循环的主要步骤。这些结构还揭示了一些有助于其功能的元素，包括允许通道打开的 C 端闩锁，以及细胞外前庭中的阴离子环，有助于其高电导和钙离子通透性。对 α7 结构的比较为门控循环的映射提供了基础，并揭示了 Cys 环受体超家族中门控机制的差异。
