Fig. 1: Ca_V2.1 function and consequences of inactivation, its pore-forming subunit, and its four non-identical VSDs.

a Under normal conditions, some presynaptic Ca_V2.1 channels are available to activate (white) in response to an action potential, mediating Ca²⁺ influx into the presynaptic terminus that triggers transmitter release. Some Ca_V2.1 channels are inactivated (blue). b Prolonged depolarization or trains of action potentials induce voltage-dependent inactivation (VDI), further decreasing the number of available Ca_V2.1 channels and subsequently transmitter release. This contributes to synaptic plasticity. c The Ca_V2.1 pore-forming subunit (α_1A) contains four homologous repeats (I-IV). Membrane-spanning helices S1-S4 from each repeat comprise a voltage-sensor domain (VSD). The S5-S6 helices from each repeat form the ion-conducting pore. The auxiliary β-subunit binds between repeats I and II⁵³. The intracellular I-II linker and W-helix within the II-III linker (indigo) act as blocking particles to occlude ion conductance during VDI in related Ca_V2 channels^45,46,47,48. d Top view of α_1A (PDB: 8X90³⁸). e S4 helix sequence comparison. Positively charged residues (bold) confer voltage sensitivity to the VSDs^19,20. Amino-acid residues substituted to cysteine for fluorescence labeling in Fig. 2 are in magenta: VSD-I: E188; VSD-II: G574; VSD-III: N1340; VSD-IV: N1652.