Molecular Interactions in the Voltage Sensor Controlling Gating Properties of Ca_V Calcium Channels

Voltage-gated calcium channels (Ca_V) regulate numerous vital functions in nerve and muscle cells. To fulfill their diverse functions, the multiple members of the Ca_V channel family are activated over a wide range of voltages. Voltage sensing in potassium and sodium channels involves the sequential transition of positively charged amino acids across a ring of residues comprising the charge transfer center. In Ca_V channels, the precise molecular mechanism underlying voltage sensing remains elusive. Here we combined Rosetta structural modeling with site-directed mutagenesis to identify the molecular mechanism responsible for the specific gating properties of two Ca_V1.1 splice variants. Our data reveal previously unnoticed interactions of S4 arginines with an aspartate (D1196) outside the charge transfer center of the fourth voltage-sensing domain that are regulated by alternative splicing of the S3-S4 linker. These interactions facilitate the final transition into the activated state and critically determine the voltage sensitivity and current amplitude of these Ca_V channels. Voltage-gated calcium channels (Ca_V) translate membrane depolarization into calcium influx that regulates muscle contraction, hormone secretion, or synaptic transmission. Using computational structural modeling, site-directed mutagenesis, and electrophysiology, Tuluc et al. identified the mechanism responsible for the different voltage sensitivities of two Ca_V1.1 calcium channel splice variants.