Unitary potential (UP) depolarizations are the basic intracellular events responsible for pacemaker activity in interstitial cells of Cajal (ICCs), and are generated at intracellular sites termed “pacemaker units”. In this study, we present a mathematical model of the transmembrane ion flows and intracellular Ca2+ dynamics from a single ICC pacemaker unit acting at near-resting membrane potential. This model quantitatively formalizes the framework of a novel ICC pacemaking mechanism that has recently been proposed. Model simulations produce spontaneously rhythmic UP depolarizations with an amplitude of ∼3 mV at a frequency of 0.05 Hz. The model predicts that the main inward currents, carried by a Ca2+-inhibited nonselective cation conductance, are activated by depletion of sub-plasma-membrane [Ca2+] caused by sarcoendoplasmic reticulum calcium ATPase Ca2+ sequestration. Furthermore, pacemaker activity predicted by our model persists under simulated voltage clamp and is independent of [IP3] oscillations. The model presented here provides a basis to quantitatively analyze UP depolarizations and the biophysical mechanisms underlying their production.
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