Molecular Insights into the Gating Mechanisms of Voltage-gated Calcium Channel Ca2.3

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Jan 31

PMID 36720859

Authors

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

Affiliations

Soon will be listed here.

Abstract

High-voltage-activated R-type Ca2.3 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 Ca2.3 in complex with the α2δ1 and β1 subunits. The VSD is stabilized in the resting state. Electrophysiological experiments elucidate that the VSD 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, which is exclusively conserved in the Ca2 family, and nearby regions at the alpha-interacting domain (AID) and S4-S5 helix are identified. Further functional analyses indicate that these interactions are critical for the open-state inactivation (OSI) of Ca2 channels.

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