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Structures of the R-type human Cav2.3 channel reveal conformational crosstalk of the intracellular segments

Author

Listed:
  • Xia Yao

    (Princeton University)

  • Yan Wang

    (St. John’s University)

  • Zhifei Wang

    (St. John’s University)

  • Xiao Fan

    (Princeton University)

  • Di Wu

    (University of Oxford
    University of Oxford)

  • Jian Huang

    (Princeton University)

  • Alexander Mueller

    (Princeton University)

  • Sarah Gao

    (Princeton University)

  • Miaohui Hu

    (Princeton University)

  • Carol V. Robinson

    (University of Oxford
    University of Oxford)

  • Yong Yu

    (St. John’s University)

  • Shuai Gao

    (Princeton University
    Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, TaiKang Center for Life and Medical Sciences, Wuhan University)

  • Nieng Yan

    (Princeton University)

Abstract

The R-type voltage-gated Ca2+ (Cav) channels Cav2.3, widely expressed in neuronal and neuroendocrine cells, represent potential drug targets for pain, seizures, epilepsy, and Parkinson’s disease. Despite their physiological importance, there have lacked selective small-molecule inhibitors targeting these channels. High-resolution structures may aid rational drug design. Here, we report the cryo-EM structure of human Cav2.3 in complex with α2δ−1 and β3 subunits at an overall resolution of 3.1 Å. The structure is nearly identical to that of Cav2.2, with VSDII in the down state and the other three VSDs up. A phosphatidylinositol 4,5-bisphosphate (PIP2) molecule binds to the interface of VSDII and the tightly closed pore domain. We also determined the cryo-EM structure of a Cav2.3 mutant in which a Cav2-unique cytosolic helix in repeat II (designated the CH2II helix) is deleted. This mutant, named ΔCH2, still reserves a down VSDII, but PIP2 is invisible and the juxtamembrane region on the cytosolic side is barely discernible. Our structural and electrophysiological characterizations of the wild type and ΔCH2 Cav2.3 show that the CH2II helix stabilizes the inactivated conformation of the channel by tightening the cytosolic juxtamembrane segments, while CH2II helix is not necessary for locking the down state of VSDII.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-35026-6
    DOI: 10.1038/s41467-022-35026-6
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    References listed on IDEAS

    as
    1. 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.
    2. 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.
    3. Yanyu Zhao & Gaoxingyu Huang & Qiurong Wu & Kun Wu & Ruiqi Li & Jianlin Lei & Xiaojing Pan & Nieng Yan, 2019. "Cryo-EM structures of apo and antagonist-bound human Cav3.1," Nature, Nature, vol. 576(7787), pages 492-497, December.
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    Cited by:

    1. 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.

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