Favile, Pullan, Sanders, Koh, Lloyd, Smith, 2009

Model Status

This CellML model is known to run PCEnv to replicate the published results. Because the model is in a CellML 1.1 format (as opposed to CellML 1.0) COR is unable to run the model. However, where possible unit checking was carried out and to our knowledge they are consistent.

Model Structure

Phasic gastrointestinal (GI) muscle is able to autonomously generate rhythmic contractions independent of the enteric nervous system. The electrical activity that generates these rhythmic contractions are called slow waves, or pacemaker potentials (PP), and they are produced by a specialised group of pacemaker cells called Interstitial Cells of Cajal (ICC). They pass via gap junctions from the ICC to smooth muscle cells (SMC), activating L-type Ca2+ channels, Ca2+ influx and the contraction of the SMC. Full slow waves result from the summation of a large number of localised cellular membrane fluctuations, and are know as unitary potentials (UPs). These are generated at intracellular sites called pacemaker units, and are known to play an essential role in driving the coordinated contraction of GI muscles.

In the study described here, Richard Faville et al. have developed a mathematical model of the ICC pacemaker potential. The model can be divided into two distinct components: the bulk cytoplasm and the pacemaker units. The later have been described previously (Faville et al., 2008, and the CellML description of this model can be found here). The pacemaker unit model quantitatively describes the transmembrane ion flows and intracellular Ca2+ dynamics from a single ICC pacemaker unit, and a schematic diagram of this model can be seen in the figure immediately below.

A schematic diagram of the pacemaker unit illustrating all the compartmental volumes and ionic conductances, together with their interactions.

The bulk cytoplasmic model describes the ionic conductances that have been identified as being essential for the for coordinated ICC activity, but were absent in the pacemaker unit description, namely 2 calcium currents; I_CaT and I_Ca(Ext); several potassium currents; I_K(v1.1), I_K(ERG), I_K(Ca), and I_K(B); and finally, a non-specific inward leakage current (I_L). In addition, the bulk cytoplasmic model also describes intracellular calcium fluxes, and defines state variable derivatives such as the cytosolic calcium concentration (C_Cy), and the membrane potential (Vm).

The combined model is described here in CellML 1.1. The pacemaker unit is defined and is imported into the bulk cytoplasm 7 times (note that the number of pacemaker units that could be used within the modelling framework is completely arbitrary, however 7 appears to be the minimum number required to adequately describe the pacemaker potential depolarisation). In order to embed the pacemaker model within the bulk cytoplasm modelling framework the original pacemaker model had to be modified slightly. This is because the it was only representative of pacemaker activity near the resting membrane potential of -70mV. In its modified form and embedded within the bulk cytoplasm it is now capable of simulating pacemaker activity under conditions of membrane depolarisation (Vm > -60mV). A full schematic diagram of the combined model is illustrated in the figure below.

A full schematic diagram of the bulk cytoplasm model with the imported pacemaker units illustrating all the compartmental volumes and ionic conductances, together with their interactions.