ALLOSTERIC GATING OF A LARGE-CONDUCTANCE CA-ACTIVATED K+ CHANNEL

Large-conductance Ca-activated potassium channels (BK channels) are un iquely sensitive to both membrane potential and intracellular Ca2+. Re cent work has demonstrated that in the gating of these channels there are voltage-sensitive steps that are separate from Ca2+ binding steps. Based on this result and the macroscopic steady state and kinetic pro perties of the cloned BK channel mslo, we have recently proposed a gen eral kinetic scheme to describe the interaction between voltage and Ca 2+ in the gating of the mslo channel (Cui, J., D.H. Cox, and R.W. Aldr ich. 1997. J. Gen. Physiol. In press.). This scheme supposes that the channel exists in two main conformations, closed and open. The conform ational change between closed and open is voltage dependent. Ca2+ bind s to both the closed and open conformations, but on average binds more tightly to the open conformation and thereby promotes channel opening . Here we describe the basic properties of models of this form and tes t their ability to mimic mslo macroscopic steady state and kinetic beh avior. The simplest form of this scheme corresponds to a voltage-depen dent version of the Monod-Wyman-Changeux (MWC) model of allosteric pro teins. The success of voltage-dependent MWC models in describing many aspects of mslo gating suggests that these channels may share a common molecular mechanism with other allosteric proteins whose behaviors ha ve been modeled using the MWC formalism. We also demonstrate how this scheme can arise as a simplification of a more complex scheme that is based on the premise that the channel is a homotetramer with a single Ca2+ binding site and a single voltage sensor in each subunit. Aspects of the mule data not well fitted by the simplified scheme will likely be better accounted for by this more general scheme. The kinetic sche mes discussed in this paper may be useful in interpreting the effects of BK channel modifications or mutations.