 Voltage sensors, selectivity filter, and the gate work together in a coordinated manner to open and close TPCs for regulation of ion conductance.The VSD2 domain contains a normal voltage sensing motif, arginine residues R1, R2 and R3 and alpha helix S10, in respect to other voltage-gated ion channels structures, but this domain adopts a distinct conformation in the resting state of a voltage sensor.Luminal calcium acts as a TPC1 inhibitor, preventing ion conductance.