Dataset Information

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

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.

SUBMITTER: Gao Y

PROVIDER: S-EPMC9889812 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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

Gao Yiwei Y Xu Shuai S Cui Xiaoli X Xu Hao H Qiu Yunlong Y Wei Yiqing Y Dong Yanli Y Zhu Boling B Peng Chao C Liu Shiqi S Zhang Xuejun Cai XC Sun Jianyuan J Huang Zhuo Z Zhao Yan Y

Nature communications 20230131 1

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 channe ...[more]

PMID: 36720859

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Project description:L-type voltage-gated calcium channels (LTCCs) are implicated in several psychiatric disorders that are comorbid with alcoholism and involve amygdala dysfunction. Within the amygdala, the central nucleus (CeA) is critical in acute alcohol's reinforcing actions, and its dysregulation in human alcoholics drives their negative emotional state and motivation to drink. Here we investigated the specific role of CeA LTCCs in the effects of acute alcohol at the molecular, cellular physiology, and behavioral levels, and their potential neuroadaptation in alcohol-dependent rats. Alcohol increases CeA activity (neuronal firing rates and GABA release) in naive rats by engaging LTCCs, and intra-CeA LTCC blockade reduces alcohol intake in nondependent rats. Alcohol dependence reduces CeA LTCC membrane abundance and disrupts this LTCC-based mechanism; instead, corticotropin-releasing factor type 1 receptors (CRF1s) mediate alcohol's effects on CeA activity and drive the escalated alcohol intake of alcohol-dependent rats. Collectively, our data indicate that alcohol dependence functionally alters the molecular mechanisms underlying the CeA's response to alcohol (from LTCC- to CRF1-driven). This mechanistic switch contributes to and reflects the prominent role of the CeA in the negative emotional state that drives excessive drinking.SIGNIFICANCE STATEMENT The central amygdala (CeA) plays a critical role in the development of alcohol dependence. As a result, much preclinical alcohol research aims to identify relevant CeA neuroadaptions that promote the transition to dependence. Here we report that acute alcohol increases CeA neuronal activity in naive rats by engaging L-type calcium channels (LTCCs) and that intra-CeA LTCC blockade reduces alcohol intake in nondependent rats. Alcohol dependence disrupts this LTCC-based mechanism; instead, corticotropin-releasing factor type 1 receptors (CRF1s) mediate alcohol's effects on CeA activity and drive the escalated alcohol intake of alcohol-dependent rats. This switch reflects the important role of the CeA in the pathophysiology of alcohol dependence and represents a new potential avenue for therapeutic intervention during the transition period.

Dataset Information

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

Publications

Molecular insights into the gating mechanisms of voltage-gated calcium channel Ca<sub>V</sub>2.3.

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