Ion Channels, Action Potentials and Ca 2+ Handling in Human Pancreatic Beta-Cells. a Computational Approach

Abstract

In this study, we examined the ionic mechanisms mediating depolarization-induced spike activity in human pancreatic beta-cells. We formulated a Hodgkin-Huxley-type ionic model for the action potential (AP) in these cells based on experimental voltage- and current-clamp results from our laboratory and literature. The model contains the equations for the currents: inward L-, P/Q and T-type Ca2+, a “rapid” delayed rectifier K+, the voltage-gated and Ca2+-activated K+ (BK-type), a voltage-independent Ca2+-activated K+ (SK-type), an ATP-sensitive K+, a plasma membrane calcium pump, a voltage-gated Na+ and a Na+ background. Ionic model is coupled to an equation describing intracellular Ca2+ homeostasis. The model simulates the behavior of human beta-cell APs under a wide range of experimental conditions, including changes in the period and amplitude of AP in response to glucose challenge and changes in islet electrical activity due to K+, Na+ and Ca+ channel blockade. The model was used to study the role of specific ionic currents in human pancreatic beta-cell firing. Particularly, modeling supports the importance of constitutively active tetrodotoxin-sensitive Na+ and voltage-gated Ca2+-activated K+ channels (BK-type) in maintaining spontaneous spikes. This model provides acceptable fits to voltage-clamp, action potential and Ca2+ concentration data and can be used to seek biophysically based explanations of the electrophysiological activity and Ca2+ influx in human beta-cells for in silico analysis of physiological conditions and channel modulator actions.