The Journal of General Physiology
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Published online Apr 26 2004. doi:10.1085/jgp.200409052
The Rockefeller University Press, 0022-1295 $8.00
JGP, Volume 123, Number 5, 475-489
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Mapping the BKCa Channel's "Ca2+ Bowl"

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 BKCa 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 BKCa channel's intracellular domain. Thus, much of our data supports the conclusion that Ca2+ binds to the BKCa 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 • BKCa • potassium channel • Ca2+ bowl • Ca2+ binding


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