Barium ions selectively activate BK channels via the Ca²⁺-bowl site

Activation of Ca²⁺-dependent BK channels is increased via binding of micromolar Ca²⁺ to two distinct high-affinity sites per BK α-subunit. One site, termed the Ca²⁺ bowl, is embedded within the second RCK domain (RCK2; regulator of conductance for potassium) of each α-subunit, while oxygen-containing residues in the first RCK domain (RCK1) have been linked to a separate Ca²⁺ ligation site. Although both sites are activated by Ca²⁺ and Sr²⁺, Cd²⁺ selectively favors activation via the RCK1 site. Divalent cations of larger ionic radius than Sr²⁺ are thought to be ineffective at activating BK channels. Here we show that Ba²⁺, better known as a blocker of K⁺ channels, activates BK channels and that this effect arises exclusively from binding at the Ca²⁺-bowl site. Compared with previous estimates for Ca²⁺ bowl-mediated activation by Ca ²⁺, the affinity of Ba²⁺ to the Ca²⁺ bowl is reduced about fivefold, and coupling of binding to activation is reduced from ∼3.6 for Ca²⁺ to about ∼2.8 for Ba²⁺. These results support the idea that ionic radius is an important determinant of selectivity differences among different divalent cations observed for each Ca²⁺-binding site.