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© The Rockefeller University Press, 0022-1295/1999//93/ $5.00
Journal of General Physiology, Volume 114, Number 1, 1999

Original Article

Gating Kinetics of Single Large-Conductance Ca2+-Activated K+ Channels in High Ca2+ Suggest a Two-Tiered Allosteric Gating Mechanism{image}

Brad S. Rothberga and Karl L. Maglebya

a From the Department of Physiology and Biophysics, University of Miami School of Medicine, Miami, Florida 33101-6430
Dept. of Physiology and Biophysics (R-430), University of Miami School of Medicine, Miami, FL 33101-6430.Fax: 305-243-6898;

kmagleby{at}miami.edu

The Ca2+-dependent gating mechanism of large-conductance calcium-activated K+ (BK) channels from cultured rat skeletal muscle was examined from low (4 µM) to high (1,024 µM) intracellular concentrations of calcium (Ca2+i) using single-channel recording. Open probability (Po) increased with increasing Ca2+i (K0.5 11.2 ± 0.3 µM at +30 mV, Hill coefficient of 3.5 ± 0.3), reaching a maximum of ~0.97 for Ca2+i ~ 100 µM. Increasing Ca2+i further to 1,024 µM had little additional effect on either Po or the single-channel kinetics. The channels gated among at least three to four open and four to five closed states at high levels of Ca2+i (>100 µM), compared with three to four open and five to seven closed states at lower Ca2+i. The ability of kinetic schemes to account for the single-channel kinetics was examined with simultaneous maximum likelihood fitting of two-dimensional (2-D) dwell-time distributions obtained from low to high Ca2+i. Kinetic schemes drawn from the 10-state Monod-Wyman-Changeux model could not describe the dwell-time distributions from low to high Ca2+i. Kinetic schemes drawn from Eigen's general model for a ligand-activated tetrameric protein could approximate the dwell-time distributions but not the dependency (correlations) between adjacent intervals at high Ca2+i. However, models drawn from a general 50 state two-tiered scheme, in which there were 25 closed states on the upper tier and 25 open states on the lower tier, could approximate both the dwell-time distributions and the dependency from low to high Ca2+i. In the two-tiered model, the BK channel can open directly from each closed state, and a minimum of five open and five closed states are available for gating at any given Ca2+i. A model that assumed that the apparent Ca2+-binding steps can reach a maximum rate at high Ca2+i could also approximate the gating from low to high Ca2+i. The considered models can serve as working hypotheses for the gating of BK channels.

Key Words: BK channel • KCa channel • Monod-Wyman-Changeux • Eigen • Markov

© 1999 The Rockefeller University Press


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