Closed-state inactivation and pore-blocker modulation mechanisms of human CaV2.2

作者：Yanli Dong, Yiwei Gao, Shuai Xu, Yuhang Wang, Zhuoya Yu, Yue Li, Bin Li, Yuan Tian, Bei Yang, Xuejun C. Zhang, Daohua Jiang, Zhuo Huang, Yan Zhao · 发表于：Cell Reports · 年份：2021 · DOI：10.1016/j.celrep.2021.109931 · 被引用次数：68 · 研究领域：Ion channel regulation and function、Cardiac electrophysiology and arrhythmias、Advanced Electron Microscopy Techniques and Applications

N-type voltage-gated calcium (Ca V ) channels mediate Ca 2+ influx at presynaptic terminals in response to action potentials and play vital roles in synaptogenesis, release of neurotransmitters, and nociceptive transmission. Here, we elucidate a cryo-electron microscopy (cryo-EM) structure of the human Ca V 2.2 complex in apo, ziconotide-bound, and two Ca V 2.2-specific pore blockers-bound states. The second voltage-sensing domain (VSD) is captured in a resting-state conformation, trapped by a phosphatidylinositol 4,5-bisphosphate (PIP 2 ) molecule, which is distinct from the other three VSDs of Ca V 2.2, as well as activated VSDs observed in previous structures of Ca V channels. This structure reveals the molecular basis for the unique inactivation process of Ca V 2.2 channels, in which the intracellular gate formed by S6 helices is closed and a W-helix from the domain II–III linker stabilizes closed-state inactivation. The structures of this inactivated, drug-bound complex lay a solid foundation for developing new state-dependent blockers for treatment of chronic pain.