Multiple regulatory sites in large-conductance calcium-activated potassium channels.
Large conductance, Ca(2+)- and voltage-activated K(+) channels (BK) respond to two distinct physiological signals -- membrane voltage and cytosolic Ca(2+) (refs 1, 2). Channel opening is regulated by changes in Ca(2+) concentration spanning 0.5 micro M to 50 mM (refs 2-5), a range of Ca(2+) sensitivity unusual among Ca(2+)-regulated proteins. Although voltage regulation arises from mechanisms shared with other voltage-gated channels, the mechanisms of Ca(2+) regulation remain largely unknown. One potential Ca(2+)-regulatory site, termed the 'Ca(2+) bowl', has been located to the large cytosolic carboxy terminus. 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 Ca(2+) bowl, accounts for all physiological regulation of BK channels by Ca(2+); the other site contributes to effects of millimolar divalent cations that may mediate physiological regulation by cytosolic Mg(2+) (refs 5, 13). Independent regulation by multiple sites explains the large concentration range over which BK channels are regulated by Ca(2+). This allows BK channels to serve a variety of physiological roles contingent on the Ca(2+) concentration to which the channels are exposed.
Department of Anesthesiology, Washington University School of Medicine, Box 8054, St. Louis, Missouri 63110, USA.
Xiao-Ming
XM
Xia
Xuhui
X
Zeng
Christopher J
CJ
Lingle
D000494:Allosteric Regulation / Q000187:drug effects; D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002413:Cations, Divalent / Q000494:pharmacology; D017124:Conserved Sequence; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004553:Electric Conductivity; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008274:Magnesium / Q000494:pharmacology; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000187:drug effects; D021122:Protein Subunits
D002413:Cations, Divalent; D029721:Drosophila Proteins; D029968:Escherichia coli Proteins; C465449:Kcnma1 protein, mouse; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D021122:Protein Subunits; D008274:Magnesium; D011188:Potassium; D002118:Calcium