Stepwise deactivation of VSDs of Na _v channels. Cartoon depiction of the sequential deactivation of the Na_v1.5 VSD in response to membrane potential changes. The S4 helix (blue) moves relative to static S1–S3 (gray), with negatively (−) charged countercharged residues (red) and the HCS residue (green). The S4 positively (+) charged gating-charge residues adopt an up conformation under depolarized potential and transition to a down conformation as the potential recovers, illustrating the VSD’s dynamic nature. The countercharges above the HCS from helices (S1–S3) are situated in an extracellular negatively charged cluster (ENC) and are referred to as S1E, S2E, and S3E. Similarly, those closer to the cytoplasmic region occupy the intracellular negatively charged cluster (INC) and are referred to as S1I, S2I, and S3I.