RESUMO
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.
Assuntos
Canais de Cloreto/metabolismo , Motilidade Gastrointestinal/fisiologia , Células Intersticiais de Cajal/fisiologia , Animais , Anoctamina-1 , Cálcio/metabolismo , Simulação por Computador , Camundongos , Modelos Biológicos , Contração Muscular/fisiologia , Músculo Liso/metabolismoRESUMO
Gastrointestinal motility research is progressing rapidly, leading to significant advances in the last 15 years in understanding the cellular mechanisms underlying motility, following the discovery of the central role played by the interstitial cells of Cajal (ICC). As experimental knowledge of ICC physiology has expanded, biophysically based modeling has become a valuable tool for integrating experimental data, for testing hypotheses on ICC pacemaker mechanisms, and for applications in in silico studies including in multiscale models. This review is focused on the cellular electrophysiology of ICC. Recent evidence from both experimental and modeling domains have called aspects of the existing pacemaker theories into question. Therefore, current experimental knowledge of ICC pacemaker mechanisms is examined in depth, and current theories of ICC pacemaking are evaluated and further developed. Existing biophysically based ICC models and their physiological foundations are then critiqued in light of the recent advances in experimental knowledge, and opportunities to improve these models are identified. The review concludes by examining several potential clinical applications of biophysically based ICC modeling from the subcellular through to the organ level, including ion channelopathies and ICC network degradation.
RESUMO
Gastrointestinal slow waves are generated within networks of interstitial cells of Cajal (ICCs). In the intact tissue, slow waves are entrained to neighboring ICCs with higher intrinsic frequencies, leading to active propagation of slow waves. Degradation of ICC networks in humans is associated with motility disorders; however, the pathophysiological mechanisms of this relationship are uncertain. A recently developed biophysically based mathematical model of ICC was adopted and updated to simulate entrainment of slow waves. Simulated slow wave propagation was successfully entrained in a one-dimensional model, which contained a gradient of intrinsic frequencies. Slow wave propagation was then simulated in tissue models which contained a realistic two-dimensional microstructure of the myenteric ICC networks translated from wild-type (WT) and 5-HT(2B) knockout (degraded) mouse jejunum. The results showed that the peak current density in the WT model was 0.49 muA mm(-2) higher than the 5-HT(2B) knockout model, and the intracellular Ca(2+) density after 400 ms was 0.26 mM mm(-2) higher in the WT model. In conclusion, tissue-specific models of slow waves are presented, and simulations quantitatively demonstrated physiological differences between WT and 5-HT(2B) knockout models. This study provides a framework for evaluating how ICC network degradation may impair slow wave propagation and ultimately motility and transit.