Nature Communications, 31 January, 2023, DOI：https://doi.org/10.1038/s41467-023-36260-2

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

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

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.

Article link：https://www.nature.com/articles/s41467-023-36260-2