Identification of structures for ion channel kinetic models

Markov models of ion channel dynamics have evolved as experimental advances have improved our understanding of channel function. Past studies have examined limited sets of various topologies for Markov models of channel dynamics. We present a systematic method for identification of all possible Markov model topologies using experimental data for two types of native voltage-gated ion channel currents: mouse atrial sodium currents and human left ventricular fast transient outward potassium currents. Successful models identified with this approach have certain characteristics in common, suggesting that aspects of the model topology are determined by the experimental data. Incorporating these channel models into cell and tissue simulations to assess model performance within protocols that were not used for training provided validation and further narrowing of the number of acceptable models. The success of this approach suggests a channel model creation pipeline may be feasible where the structure of the model is not specified a priori.Author summary: Markov models of ion channel dynamics have evolved as experimental advances have improved our understanding of channel function. Past studies have examined limited sets of various structures for Markov models of channel dynamics. Here, we present a computational routine designed to thoroughly search for Markov model topologies for simulating whole-cell currents. We tested this method on two distinct types of voltage-gated cardiac ion channels and found the number of states and connectivity required to recapitulate experimentally observed kinetics. Successful models identified with this approach have certain characteristics in common, suggesting that model structures are determined by the experimental data. Incorporation of these models into higher scale action potential and cable (an approximation of one-dimensional action potential propagation) simulations, identified key channel phenomena that were required for proper function. These methods provide a route to create functional channel models that can be used for action potential simulation without pre-defining their structure ahead of time.