Mechanisms Responsible for ω-Pore Currents in Ca_v Calcium Channel Voltage-Sensing Domains

Mutations of positively charged amino acids in the S4 transmembrane segment of a voltage-gated ion channel form ion-conducting pathways through the voltage-sensing domain, named ω-current. Here, we used structure modeling and MD simulations to predict pathogenic ω-currents in Ca_V1.1 and Ca_V1.3 Ca²⁺ channels bearing several S4 charge mutations. Our modeling predicts that mutations of Ca_V1.1-R1 (R528H/G, R897S) or Ca_V1.1-R2 (R900S, R1239H) linked to hypokalemic periodic paralysis type 1 and of Ca_V1.3-R3 (R990H) identified in aldosterone-producing adenomas conducts ω-currents in resting state, but not during voltage-sensing domain activation. The mechanism responsible for the ω-current and its amplitude depend on the number of charges in S4, the position of the mutated S4 charge and countercharges, and the nature of the replacing amino acid. Functional characterization validates the modeling prediction showing that Ca_V1.3-R990H channels conduct ω-currents at hyperpolarizing potentials, but not upon membrane depolarization compared with wild-type channels.