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

• Published in: American journal of physiology: Gastrointestinal and liver physiology Vol. 306; no. 8; p. G711
• Main Authors: Lees-Green, Rachel, Gibbons, Simon J, Farrugia, Gianrico, Sneyd, James, Cheng, Leo K
• Format: Journal Article
• Language: English
• Published: United States 15-04-2014
• Subjects: Animals; Anoctamin-1; Calcium - metabolism; Chloride Channels - metabolism; Computer Simulation; Gastrointestinal Motility - physiology; Interstitial Cells of Cajal - physiology; Mice; Models, Biological; Muscle Contraction - physiology; Muscle, Smooth - metabolism; mathematical model; anoctamin 1; interstitial cells of Cajal; store-operated calcium entry
• ISSN: 1522-1547
• DOI: 10.1152/ajpgi.00449.2013

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.