Understanding how heterogeneous cellular responses emerge from cell-to-cell variations in expression and function of subcellular components is of general interest. Here, we focus on human insulin-secreting beta-cells, which are believed to constitute a population in which heterogeneity is of physiological importance. We exploit recent single-cell electrophysiological data that allow biologically realistic population modeling of human beta-cells that accounts for cellular heterogeneity and correlation between ion channel parameters. To investigate how ion channels influence the dynamics of our updated mathematical model of human pancreatic beta-cells, we explore several machine learning techniques to determine which model parameters are important for determining the qualitative patterns of electrical activity of the model cells. As expected, K＋ channels promote absence of activity, but once a cell is active, they increase the likelihood of having action potential firing. HERG channels were of great importance for determining cell behavior in most of the investigated scenarios. Fast bursting is influenced by the time scales of ion channel activation and, interestingly, by the type of Ca2＋ channels coupled to BK channels in BK-CaV complexes. Slow, metabolically driven oscillations are promoted mostly by K(ATP) channels. In summary, combining population modeling with machine learning analysis provides insight into the model and generates new hypotheses to be investigated both experimentally, via simulations and through mathematical analysis.
Keywords: Action potential; Bursting; Classification trees; Electrical activity; Logistic regression; Mathematical modeling; Random forest.
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