Molecular insights into the gating mechanisms of voltage-gated calcium channel Ca<sub>V</sub>2.3.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 36720859.
- Also identified by DOI 10.1038/s41467-023-36260-2 and PMC identifier 9889812.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
High-voltage-activated R-type Ca<sub>V</sub>2.3 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<sub>V</sub>2.3 in complex with the α2δ1 and β1 subunits. The VSD<sub>II</sub> is stabilized in the resting state. Electrophysiological experiments elucidate that the VSD<sub>II</sub> 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<sub>II</sub>, which is exclusively conserved in the Ca<sub>V</sub>2 family, and nearby regions at the alpha-interacting domain (AID) and S4-S5<sub>II</sub> helix are identified. Further functional analyses indicate that these interactions are critical for the open-state inactivation (OSI) of Ca<sub>V</sub>2 channels.
Medical subject headings
- Calcium Channels, R-Type
- Cation Transport Proteins