Putative model of Cu²⁺ interaction with the gating machinery of Ca_v2.3. Residues responsible for Cu²⁺ binding in Ca_v2.3 (H111, H179, and H183) were mapped onto the structural model of a voltage-gated potassium channel (Chanda et al., 2005; Campos et al., 2007). Only the S1–S4 segments from the first domain are shown. (A) In closed conformation, histidines of IS1–IS2 and IS3–IS4 loops of Ca_v2.3 are situated close to each other and can bind Cu²⁺ if it is present in the solution. The green sphere illustrates a possible position for Cu²⁺. (B) Upon channel opening, histidines are moved apart by the gating machinery, which apparently disrupts the binding pocket and releases Cu²⁺ from the binding site.