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

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

doi:10.1038/s41467-023-36260-2

Molecular insights into the gating mechanisms of voltage-gated calcium channel Ca_V2.3

Nat Commun. 2023 Jan 31;14(1):516. doi: 10.1038/s41467-023-36260-2.

Authors

Yiwei Gao^#^{1

2

3}, Shuai Xu^#⁴, Xiaoli Cui^#^{2

3

5}, Hao Xu^{1

6}, Yunlong Qiu^{1

2

3}, Yiqing Wei^{1

2

3}, Yanli Dong^{1

2

3}, Boling Zhu⁷, Chao Peng⁴, Shiqi Liu⁴, Xuejun Cai Zhang^{1

2

3}, Jianyuan Sun^{2

3

8

9}, Zhuo Huang^{10

11}, Yan Zhao^{12

13

14}

Affiliations

¹ National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
² State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, China.
³ College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
⁴ State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China.
⁵ Chinese Institute for Brain Research, Beijing, China.
⁶ Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
⁷ Center for Biological Imaging, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
⁸ Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China.
⁹ The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China.
¹⁰ State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China. huangz@hsc.pku.edu.cn.
¹¹ IDG/McGovern Institute for Brain Research, Peking University, Beijing, China. huangz@hsc.pku.edu.cn.
¹² National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. zhaoy@ibp.ac.cn.
¹³ State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, China. zhaoy@ibp.ac.cn.
¹⁴ College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China. zhaoy@ibp.ac.cn.

^# Contributed equally.

Abstract

High-voltage-activated R-type Ca_V2.3 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 Ca_V2.3 in complex with the α2δ1 and β1 subunits. The VSD_II is stabilized in the resting state. Electrophysiological experiments elucidate that the VSD_II 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 S6_II, which is exclusively conserved in the Ca_V2 family, and nearby regions at the alpha-interacting domain (AID) and S4-S5_II helix are identified. Further functional analyses indicate that these interactions are critical for the open-state inactivation (OSI) of Ca_V2 channels.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Calcium Channels, R-Type* / physiology
Cation Transport Proteins* / physiology
Cryoelectron Microscopy
Humans

Substances

CACNA1E protein, human
Calcium Channels, R-Type
Cation Transport Proteins