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Letters to Nature

Nature 418, 880-884 (22 August 2002) | doi:10.1038/nature00956; Received 16 April 2002; Accepted 19 June 2002

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Multiple regulatory sites in large-conductance calcium-activated potassium channels

Xiao-Ming Xia, Xuhui Zeng & Christopher J. Lingle

  1. Department of Anesthesiology, Washington University School of Medicine, Box 8054, St. Louis, Missouri 63110, USA

Correspondence to: Christopher J. Lingle Correspondence and requests for materials should be addressed to C.J.L. (e-mail: Email: clingle@morpheus.wustl.edu).

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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 microM 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.