Mechanism of magnesium activation of calcium-activated potassium channels

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Abstract
Large-conductance (BK type) Ca2+-dependent K+ channels are essential for modulating muscle contraction and neuronal activities such as synaptic transmission and hearing1,2,3,4,5. BK channels are activated by membrane depolarization and intracellular Ca2+ and Mg2+ (refs 6–10). The energy provided by voltage, Ca2+ and Mg2+ binding are additive in activating the channel, suggesting that these signals open the activation gate through independent pathways9,11. Here we report a molecular investigation of a Mg2+-dependent activation mechanism. Using a combined site-directed mutagenesis and structural analysis, we demonstrate that a structurally new Mg2+-binding site in the RCK/Rossman fold domain—an intracellular structural motif that immediately follows the activation gate S6 helix12,13,14,15—is responsible for Mg2+-dependent activation. Mutations that impair or abolish Mg2+ sensitivity do not affect Ca2+ sensitivity, and vice versa. These results indicate distinct structural pathways for Mg2+- and Ca2+-dependent activation and suggest a possible mechanism for the coupling between Mg2+ binding and channel opening.