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Side-chains Essential for Ca²⁺ Sensing

Lin Bao, Christina Kaldany, Ericka C. Holmstrand, and Daniel H. Cox

Molecular Cardiology Research Institute, New England Medical Center, and the Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111

Address correspondence to Daniel H. Cox, 750 Washington St., NEMC Hospitals, Box 7868, Boston, MA 02111. Fax: (617) 636-0576; email: dan.cox{at}tufts.edu

There is controversy over whether Ca²⁺ binds to the BK_Ca channel's intracellular domain or its integral-membrane domain and over whether or not mutations that reduce the channel's Ca²⁺ sensitivity act at the point of Ca²⁺ coordination. One region in the intracellular domain that has been implicated in Ca²⁺ sensing is the "Ca²⁺ bowl". This region contains many acidic residues, and large Ca²⁺-bowl mutations eliminate Ca²⁺ sensing through what appears to be one type of high-affinity Ca²⁺-binding site. Here, through site-directed mutagenesis we have mapped the residues in the Ca²⁺ bowl that are most important for Ca²⁺ sensing. We find acidic residues, D898 and D900, to be essential, and we find them essential as well for Ca²⁺ binding to a fusion protein that contains a portion of the BK_Ca channel's intracellular domain. Thus, much of our data supports the conclusion that Ca²⁺ binds to the BK_Ca channel's intracellular domain, and they define the Ca²⁺ bowl's essential Ca²⁺-sensing motif. Overall, however, we have found that the relationship between mutations that disrupt Ca²⁺ sensing and those that disrupt Ca²⁺ binding is not as strong as we had expected, a result that raises the possibility that, when examined by gel-overlay, the Ca²⁺ bowl may be in a nonnative conformation.

Key Words: mSlo • BK_Ca • potassium channel • Ca²⁺ bowl • Ca²⁺ binding

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