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Molecular insights into the gating mechanisms of voltage-gated calcium channel CaV2.3

Author

Listed:
  • Yiwei Gao

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Shuai Xu

    (Peking University Health Science Center)

  • Xiaoli Cui

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Chinese Institute for Brain Research)

  • Hao Xu

    (Chinese Academy of Sciences
    University of Science and Technology of China)

  • Yunlong Qiu

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yiqing Wei

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yanli Dong

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Boling Zhu

    (Chinese Academy of Sciences)

  • Chao Peng

    (Peking University Health Science Center)

  • Shiqi Liu

    (Peking University Health Science Center)

  • Xuejun Cai Zhang

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Jianyuan Sun

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions)

  • Zhuo Huang

    (Peking University Health Science Center
    Peking University)

  • Yan Zhao

    (Chinese Academy of Sciences
    Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

Abstract

High-voltage-activated R-type CaV2.3 channel plays pivotal roles in many physiological activities and is implicated in epilepsy, convulsions, and other neurodevelopmental impairments. Here, we determine the high-resolution cryo-electron microscopy (cryo-EM) structure of human CaV2.3 in complex with the α2δ1 and β1 subunits. The VSDII is stabilized in the resting state. Electrophysiological experiments elucidate that the VSDII is not required for channel activation, whereas the other VSDs are essential for channel opening. The intracellular gate is blocked by the W-helix. A pre-W-helix adjacent to the W-helix can significantly regulate closed-state inactivation (CSI) by modulating the association and dissociation of the W-helix with the gate. Electrostatic interactions formed between the negatively charged domain on S6II, which is exclusively conserved in the CaV2 family, and nearby regions at the alpha-interacting domain (AID) and S4-S5II helix are identified. Further functional analyses indicate that these interactions are critical for the open-state inactivation (OSI) of CaV2 channels.

Suggested Citation

  • Yiwei Gao & Shuai Xu & Xiaoli Cui & Hao Xu & Yunlong Qiu & Yiqing Wei & Yanli Dong & Boling Zhu & Chao Peng & Shiqi Liu & Xuejun Cai Zhang & Jianyuan Sun & Zhuo Huang & Yan Zhao, 2023. "Molecular insights into the gating mechanisms of voltage-gated calcium channel CaV2.3," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36260-2
    DOI: 10.1038/s41467-023-36260-2
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    References listed on IDEAS

    as
    1. Shuai Gao & Xia Yao & Nieng Yan, 2021. "Structure of human Cav2.2 channel blocked by the painkiller ziconotide," Nature, Nature, vol. 596(7870), pages 143-147, August.
    2. Jianping Wu & Zhen Yan & Zhangqiang Li & Xingyang Qian & Shan Lu & Mengqiu Dong & Qiang Zhou & Nieng Yan, 2016. "Structure of the voltage-gated calcium channel Cav1.1 at 3.6 Å resolution," Nature, Nature, vol. 537(7619), pages 191-196, September.
    3. Julia Benkert & Simon Hess & Shoumik Roy & Dayne Beccano-Kelly & Nicole Wiederspohn & Johanna Duda & Carsten Simons & Komal Patil & Aisylu Gaifullina & Nadja Mannal & Elena Dragicevic & Desirée Spaich, 2019. "Cav2.3 channels contribute to dopaminergic neuron loss in a model of Parkinson’s disease," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    4. Lingli He & Zhuoya Yu & Ze Geng & Zhuo Huang & Changjiang Zhang & Yanli Dong & Yiwei Gao & Yuhang Wang & Qihao Chen & Le Sun & Xinyue Ma & Bo Huang & Xiaoqun Wang & Yan Zhao, 2022. "Structure, gating, and pharmacology of human CaV3.3 channel," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    5. Yongqing Liu & Shirong Lai & Weining Ma & Wei Ke & Chan Zhang & Shumeng Liu & Yu Zhang & Fei Pei & Shaoyi Li & Ming Yi & Yousheng Shu & Yongfeng Shang & Jing Liang & Zhuo Huang, 2017. "CDYL suppresses epileptogenesis in mice through repression of axonal Nav1.6 sodium channel expression," Nature Communications, Nature, vol. 8(1), pages 1-17, December.
    6. Xia Yao & Yan Wang & Zhifei Wang & Xiao Fan & Di Wu & Jian Huang & Alexander Mueller & Sarah Gao & Miaohui Hu & Carol V. Robinson & Yong Yu & Shuai Gao & Nieng Yan, 2022. "Structures of the R-type human Cav2.3 channel reveal conformational crosstalk of the intracellular segments," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
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