General structure and potential Zn²⁺-binding sites in Ca_v2.3 channels. (A) General structure and transmembrane topology of Ca_v2.3 channels along with residues that have been implicated in the effects of Zn²⁺ and/or protons. Three nonconserved histidine residues in domain I (indicated in orange) have been linked to gating modulation by Zn²⁺, other d-block metal ions, and (for underlined residues) protons (Cens et al., 2011; Shcheglovitov et al., 2012; Kang et al., 2007). A nonconserved histidine residue in the p-loop of domain I (indicated in green) has been linked to proton-induced changes in single-channel conductance (Cens et al., 2011). An EF hand–like motif in the S5-H5 region of domain III (indicated in light blue) that is present in all HVA channels has been implicated in their differential sensitivity to Zn²⁺ (Sun et al., 2007). (B) Scheme illustrating possible reactions of histidine residues with protons (left), Zn²⁺ ions (bottom), or DEPC (right).