For clarity, only two of the four KCa3.1 subunits and calmodulin (CaM) are shown. In the basal state (no calcium; left panel), the CaM C lobe (green sphere) is bound to the N-terminal segment of the calmodulin-binding domain (CBD, yellow) in KCa3.1 (Schumacher et al., 2004). The transmembrane S6 helices close off the channel on the cytoplasmic side. At the C terminus of KCa3.1 is a coiled-coil region that forms a four-helix bundle (violet cylinders; S.R.H., unpublished data). Based on coiled-coil prediction software, it is probable that the region containing His358, which is just C-terminal to the CBD, also forms a four-helix bundle (maroon cylinders), with His358 (pentagon) occupying an inward-facing ‘a’ position in the heptad repeat. This would position the four copies of His358 for coordination of a Cu(II) ion on the axis of the four-helix bundle, which would stabilize the four-helix bundle and act to resist the conformational changes induced by calcium binding to the CaM N lobe (blue sphere). An increase in intracellular calcium induces conformational changes in the CBD that partially destabilize copper binding (middle panel), providing access to His358 for phosphorylation by NDPK-B (or copper chelation by TTM). Upon phosphorylation of His358, copper binding is abrogated, and the calcium-induced conformational changes in the CBD lead to channel opening (right panel; exact mechanism not known) (Adelman et al., 2012; Sachyani et al., 2014).