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Computational modeling of anoctamin 1 calcium-activated chloride channels as pacemaker channels in interstitial cells of Cajal.
Lees-Green R, Gibbons SJ, Farrugia G, Sneyd J, Cheng LK
(2014) Am J Physiol Gastrointest Liver Physiol 306: G711-27
MeSH Terms: Animals, Anoctamin-1, Calcium, Chloride Channels, Computer Simulation, Gastrointestinal Motility, Interstitial Cells of Cajal, Mice, Models, Biological, Muscle Contraction, Muscle, Smooth
Show Abstract · Added April 26, 2016
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.
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11 MeSH Terms
Numerical metrics for automated quantification of interstitial cell of Cajal network structural properties.
Gao J, Du P, O'Grady G, Archer R, Farrugia G, Gibbons SJ, Cheng LK
(2013) J R Soc Interface 10: 20130421
MeSH Terms: Animals, Anoctamin-1, Chloride Channels, Image Processing, Computer-Assisted, Interstitial Cells of Cajal, Mice, Mice, Knockout, Models, Biological, Receptors, Serotonin, 5-HT2
Show Abstract · Added April 26, 2016
Depletion of interstitial cells of Cajal (ICC) networks is known to occur in several gastrointestinal motility disorders. Although confocal microscopy can effectively image and visualize the spatial distribution of ICC networks, current descriptors of ICC depletion are limited to cell numbers and volume computations. Spatial changes in ICC network structural properties have not been quantified. Given that ICC generate electrical signals, the organization of a network may also affect physiology. In this study, six numerical metrics were formulated to automatically determine complex ICC network structural properties from confocal images: density, thickness, hole size, contact ratio, connectivity and anisotropy. These metrics were validated and applied in proof-of-concept studies to quantitatively determine jejunal ICC network changes in mouse models with decreased (5-HT2B receptor knockout (KO)) and normal (Ano1 KO) ICC numbers, and during post-natal network maturation. Results revealed a novel remodelling phenomenon occurring during ICC depletion, namely a spatial rearrangement of ICC and the preferential longitudinal alignment. In the post-natal networks, an apparent pruning of the ICC network was demonstrated. The metrics developed here enabled the first detailed quantitative analyses of structural changes that may occur in ICC networks during depletion and development.
0 Communities
1 Members
0 Resources
9 MeSH Terms