Zn²⁺ activates large conductance Ca²⁺-activated K⁺ channel via an intracellular domain

Zinc is an essential trace element and plays crucial roles in normal development, often as an integral structural component of transcription factors and enzymes. Recent evidence suggests that intracellular Zn²⁺ functions as a signaling molecule, mediating a variety of important physiological phenomena. However, the immediate effectors of intracellular Zn²⁺ signaling are not well known. We show here that intracellular Zn²⁺ potently and reversibly activates large-conductance voltage- and Ca²⁺-activated Slo1 K⁺ (BK) channels. The full effect of Zn²⁺ requires His³⁶⁵ in the RCK1 (regulator of conductance for K⁺) domain of the channel. Furthermore, mutation of two nearby acidic residues, Asp³⁶⁷ and Glu³⁹⁹, also reduced activation of the channel by Zn²⁺, suggesting a possible structural arrangement for Zn²⁺ binding by the aforementioned residues. Extracellular Zn²⁺ activated Slo1 BK channels when coexpressed with Zn²⁺-permeable TRPM7 (transient receptor potential melastatin 7) channels. The results thus demonstrate that Slo1 BK channels represent a positive and direct effector of Zn²⁺ signaling and may participate in sculpting cellular response to an increase in intracellular Zn²⁺ concentration.