Published online 12 December 2005 doi:10.1085/jgp.200509317
The Rockefeller University Press, 0022-1295 $8.00
JGP, Volume 127, Number 1, 35-50
Effects of Multiple Metal Binding Sites on Calcium and Magnesium-dependent Activation of BK Channels
Lei Hu,
Huanghe Yang,
Jingyi Shi, and
Jianmin Cui
Department of Biomedical Engineering and Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, MO 63130
Correspondence to Jianmin Cui: jcui{at}biomed.wustl.edu
BK channels are activated by physiological concentrations of intracellular Ca2+ and Mg2+ in a variety of cells. Previous studies have identified two sites important for high-affinity Ca2+ sensing between [Ca2+]i of 0.1–100 µM and a site important for Mg2+ sensing between [Mg2+]i of 0.1–10 mM. BK channels can be also activated by Ca2+ and Mg2+ at concentrations >10 mM so that the steady-state conductance and voltage (G-V) relation continuously shifts to more negative voltage ranges when [Mg2+]i increases from 0.1–100 mM. We demonstrate that a novel site is responsible for metal sensing at concentrations 
10 mM, and all four sites affect channel activation independently. As a result, the contributions of these sites to channel activation are complex, depending on the combination of Ca2+ and Mg2+ concentrations. Here we examined the effects of each of these sites on Ca2+ and Mg2+-dependent activation and the data are consistent with the suggestion that these sites are responsible for metal binding. We provide an allosteric model for quantitative estimation of the contributions that each of these putative binding sites makes to channel activation at any [Ca2+]i and [Mg2+]i.
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