![]() Voltage-gated calcium (Ca V) channels mediate calcium influx to cells in response to changes in membrane potential 1, 2, 3. Further functional analyses indicate that these interactions are critical for the open-state inactivation (OSI) of Ca V2 channels. 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. 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. The intracellular gate is blocked by the W-helix. Electrophysiological experiments elucidate that the VSD II is not required for channel activation, whereas the other VSDs are essential for channel opening. The VSD II is stabilized in the resting state. 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. 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.
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