Modeling the kinetics of heteromeric potassium channels

Abstract

Mechanistic mathematical modeling has long been used as a tool for answering questions in cellular physiology. To mathematically describe cellular processes such as cell excitability, volume regulation, neurotransmitter release, and hormone secretion requires accurate descriptions of ion channel kinetics. One class of ion channels currently lacking a physiological model framework is the class of channels built with multiple different potassium protein subunits called heteromeric voltage gated potassium channels. Here we present a novel mathematical model for heteromeric potassium channels that captures both the number and type of protein subunits present in each channel. Key model assumptions are validated by showing our model is the reduction of a Markov model and through observations about voltage clamp data. We then show our model's success in replicating kinetic properties of concatemeric channels with different numbers of Kv1.1 and Kv1.2 subunits. Finally, through comparisons with multiple expression experiments across multiple voltage gated potassium families, we use the model to make predictions about the importance and effect of genetic mutations in heteromeric channel formation.