Allosteric control of gating mechanisms revisited: the large conductance Ca2+-activated K+ channel.
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.
Rosales
Rafael A
RA
Department of Physics and Mathematics, Faculdade de Filosofia Ciências e Letras de Ribeirão Preto, University of São Paulo, Ribeirão Preto/SP Brazil. rrosales@ffclrp.usp.br
Varanda
Wamberto A
WA
D000494:Allosteric Regulation; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015640:Ion Channel Gating; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000378:metabolism*; D008390:Markov Chains; D008954:Models, Biological; D009010:Monte Carlo Method; D011336:Probability; D015203:Reproducibility of Results
D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D002118:Calcium