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Published online Sep 26 2005. doi:10.1085/jgp.200509346
The Rockefeller University Press, 0022-1295 $8.00
JGP, Volume 126, Number 4, 393-412
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ARTICLE

 Gating and Ionic Currents Reveal How the BKCa Channel's Ca2+ Sensitivity Is Enhanced by its ß1 Subunit

Lin Bao and Daniel H. Cox

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

Correspondence to Daniel H. Cox: dan.cox{at}tufts.edu

Large-conductance Ca2+-activated K+ channels (BKCa channels) are regulated by the tissue-specific expression of auxiliary ß subunits. ß1 is predominately expressed in smooth muscle, where it greatly enhances the BKCa channel's Ca2+ sensitivity, an effect that is required for proper regulation of smooth muscle tone. Here, using gating current recordings, macroscopic ionic current recordings, and unitary ionic current recordings at very low open probabilities, we have investigated the mechanism that underlies this effect. Our results may be summarized as follows. The ß1 subunit has little or no effect on the equilibrium constant of the conformational change by which the BKCa channel opens, and it does not affect the gating charge on the channel's voltage sensors, but it does stabilize voltage sensor activation, both when the channel is open and when it is closed, such that voltage sensor activation occurs at more negative voltages with ß1 present. Furthermore, ß1 stabilizes the active voltage sensor more when the channel is closed than when it is open, and this reduces the factor D by which voltage sensor activation promotes opening by ~24% (16.8->12.8). The effects of ß1 on voltage sensing enhance the BKCa channel's Ca2+ sensitivity by decreasing at most voltages the work that Ca2+ binding must do to open the channel. In addition, however, in order to fully account for the increase in efficacy and apparent Ca2+ affinity brought about by ß1 at negative voltages, our studies suggest that ß1 also decreases the true Ca2+ affinity of the closed channel, increasing its Ca2+ dissociation constant from ~3.7 µM to between 4.7 and 7.1 µM, depending on how many binding sites are affected.

Abbreviation used in this paper: BKCa, large-conductance Ca2+-activated K+ channel.


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