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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 Slol 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 Slol BK channels when coexpressed with Zn2+ -permeable TRPM7 (transient receptor potential melastatin 7) channels. The results thus demonstrate that Sbol 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. [ABSTRACT FROM AUTHOR]