Concise Whole-Cell Modeling of BK Ca -CaV Activity Controlled by Local Coupling and Stoichiometry.

Large-conductance Ca2+ -dependent K+ (BKCa ) channels are important regulators of electrical activity. These channels colocalize and form ion channel complexes with voltage-dependent Ca2+ (CaV) channels. Recent stochastic simulations of the BKCa -CaV complex with 1:1 stoichiometry have given important insight into the local control of BKCa channels by fluctuating nanodomains of Ca2+ . However, such Monte Carlo simulations are computationally expensive, and are therefore not suitable for large-scale simulations of cellular electrical activity. In this work we extend the stochastic model to more realistic BKCa -CaV complexes with 1:n stoichiometry, and analyze the single-complex model with Markov chain theory. From the description of a single BKCa -CaV complex, using arguments based on timescale analysis, we derive a concise model of whole-cell BKCa currents, which can readily be analyzed and inserted into models of cellular electrical activity. We illustrate the usefulness of our results by inserting our BKCa description into previously published whole-cell models, and perform simulations of electrical activity in various cell types, which show that BKCa -CaV stoichiometry can affect whole-cell behavior substantially. Our work provides a simple formulation for the whole-cell BKCa current that respects local interactions in BKCa -CaV complexes, and indicates how local-global coupling of ion channels may affect cell behavior.