Computational modeling of anoctamin 1 calcium-activated chloride channels as pacemaker channels in interstitial cells of Cajal

Abstract

Interstitial cells of Cajal (ICC) act as pacemaker cells in the gastrointestinal tract by generating electrical slow waves to regulate rhythmic smooth muscle contractions. Intrinsic Ca(2+) oscillations in ICC appear to produce the slow waves by activating pacemaker currents, currently thought to be carried by the Ca(2+)-activated Cl(-) channel anoctamin 1 (Ano1). In this article we present a novel model of small intestinal ICC pacemaker activity that incorporates store-operated Ca(2+) entry and a new model of Ano1 current. A series of simulations were carried out with the ICC model to investigate current controversies about the reversal potential of the Ano1 Cl(-) current in ICC and to predict the characteristics of the other ion channels that are necessary to generate slow waves. The model results show that Ano1 is a plausible pacemaker channel when coupled to a store-operated Ca(2+) channel but suggest that small cyclical depolarizations may still occur in ICC in Ano1 knockout mice. The results predict that voltage-dependent Ca(2+) current is likely to be negligible during the slow wave plateau phase. The model shows that the Cl(-) equilibrium potential is an important modulator of slow wave morphology, highlighting the need for a better understanding of Cl(-) dynamics in ICC.