Large conductance, Ca2+- and voltage-activated K+ channels (BK) respond to two distinct physiological signals—membrane voltage and cytosolic Ca2+ (refs 1, 2). Channel opening is regulated by changes in Ca2+ concentration spanning 0.5 µM to 50 mM (refs 2–5), a range of Ca2+ sensitivity unusual among Ca2+-regulated proteins. Although voltage regulation arises from mechanisms shared with other voltage-gated channels6,7,8, the mechanisms of Ca2+ regulation remain largely unknown. One potential Ca2+-regulatory site, termed the ‘Ca2+ bowl’, has been located to the large cytosolic carboxy terminus9,10,11. Here we show that a second region of the C terminus, the RCK domain (regulator of conductance for K+ (ref. 12)), contains residues that define two additional regulatory effects of divalent cations. One site, together with the Ca2+ bowl, accounts for all physiological regulation of BK channels by Ca2+; the other site contributes to effects of millimolar divalent cations that may mediate physiological regulation by cytosolic Mg2+ (refs 5, 13). Independent regulation by multiple sites explains the large concentration range over which BK channels are regulated by Ca2+. This allows BK channels to serve a variety of physiological roles contingent on the Ca2+ concentration to which the channels are exposed14,15.
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We thank the members of our laboratory for encouragement and assistance during this work and L. Lavack for preparation and care of oocytes. We thank J. H. Steinbach, J. Nerbonne and L. Salkoff for discussions and comments on the manuscript. We also thank the Department of Anesthesiology, Washington University School of Medicine, for material support.
The authors declare that they have no competing financial interests.
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