Intracellular Mg²⁺ enhances the function of BK-type Ca²⁺-activated K⁺ channels

BK channels modulate neurotransmitter release due to their activation by voltage and Ca²⁺. Intracellular Mg²⁺ also modulates BK channels in multiple ways with opposite effects on channel function. Previous single-channel studies have shown that Mg²⁺ blocks the pore of BK channels in a voltage-dependent manner. We have confirmed this result by studying macroscopic currents of the mslol channel. We find that Mg²⁺ activates mslol BK channels independently of Ca²⁺ and voltage by preferentially binding to their open conformation. The mslo3 channel, which lacks Ca²⁺ binding sites in the tail, is not activated by Mg²⁺. However, coexpression of the mslol core and mslo3 tail produces channels with Mg²⁺ sensitMty similar to mslol channels, indicating that Mg²⁺ sites differ from Ca²⁺ sites. We discovered that Mg²⁺ also binds to Ca²⁺ sites and competitively inhibits Ca²⁺-dependent activation. Quantitative computation of these effects reveals that the overall effect of Mg²⁺ under physiological conditions is to enhance BK channel function.