Schematic showing state-dependent positions of Cd²⁺ and key charged residues in S2–S4 segments of the VSD of a single hERG1 channel subunit. According to this model, Cd²⁺ is displaced in an outward direction by basic residues in the S4 segment as it moves inward in response to membrane repolarization. (Left) VSD at depolarized potentials and Cd²⁺ in its “depolarized” coordination site. (Right) VSD at a negative transmembrane potential when all channels are closed and Cd²⁺ located in a position defined as the “repolarized” coordination site. (Middle) A putative intermediate state of the channel. K1, K525; R2, R528; R3, R531; R4, R534; D1, D456; D2, D460; D3, D509. The yellow circle represents a Cd²⁺ ion.