Allosteric control of gating mechanisms revisited: the large conductance Ca2+-activated K+ channel

Biophys J. 2009 May 20;96(10):3987-96. doi: 10.1016/j.bpj.2009.02.042.

Abstract

Large-conductance Ca(2+)-activated K(+) channels (BK) play a fundamental role in modulating membrane potential in many cell types. The gating of BK channels and its modulation by Ca(2+) and voltage has been the subject of intensive research over almost three decades, yielding several of the most complicated kinetic mechanisms ever proposed. A large number of open and closed states disposed, respectively, in two planes, named tiers, characterize these mechanisms. Transitions between states in the same plane are cooperative and modulated by Ca(2+). Transitions across planes are highly concerted and voltage-dependent. Here we reexamine the validity of the two-tiered hypothesis by restricting attention to the modulation by Ca(2+). Large single channel data sets at five Ca(2+) concentrations were simultaneously analyzed from a Bayesian perspective by using hidden Markov models and Markov-chain Monte Carlo stochastic integration techniques. Our results support a dramatic reduction in model complexity, favoring a simple mechanism derived from the Monod-Wyman-Changeux allosteric model for homotetramers, able to explain the Ca(2+) modulation of the gating process. This model differs from the standard Monod-Wyman-Changeux scheme in that one distinguishes when two Ca(2+) ions are bound to adjacent or diagonal subunits of the tetramer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Calcium / metabolism
  • Dose-Response Relationship, Drug
  • Ion Channel Gating*
  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / metabolism*
  • Markov Chains
  • Models, Biological
  • Monte Carlo Method
  • Probability
  • Reproducibility of Results

Substances

  • Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
  • Calcium