A gating lever and molecular logic gate that couple voltage and calcium sensor activation to opening in BK potassium channels

BK channels uniquely integrate voltage and calcium signaling in diverse cell types through allosteric activation of their K+-conducting pore by structurally distinct V and Ca2+ sensor domains. Here, we define mechanisms and interaction pathways that link V sensors to the pore by analyzing effects on allosteric coupling of point mutations in the context of Slo1 BK channel structure. A gating lever, mediated by S4/S5 segment interaction within the transmembrane domain, rotates to engage and stabilize the open conformation of the S6 inner pore helix upon V sensor activation. In addition, an indirect pathway, mediated by the carboxyl-terminal cytosolic domain (CTD) and C-linker that connects the CTD to S6, stabilizes the closed conformation when V sensors are at rest. Unexpectedly, this mechanism, which bypasses the covalent connections of C-linker to CTD and pore, also transduces Ca2+-dependent coupling in a manner that is completely nonadditive with voltage, analogous to the function of a digital logic (OR) gate.