A mathematical model of pacemaker activity recorded from mouse small intestine

Abstract

The pacemaker activity of interstitial cells of Cajal (ICCs) has been known to initiate the propagation of slow waves along the whole gastrointestinal tract through spontaneous and repetitive generation of action potentials. We studied the mechanism of the pacemaker activity of ICCs in the mouse small intestine and tested it using a mathematical model. The model includes ion channels, exchanger, pumps and intracellular machinery for Ca2+ regulation. The model also incorporates inositol 1,4,5-triphosphate (IP3) production and IP3-mediated Ca2+ release activities. Most of the parameters were obtained from the literature and were modified to fit the experimental results of ICCs from mouse small intestine. We were then able to compose a mathematical model that simulates the pacemaker activity of ICCs. The model generates pacemaker potentials regularly and repetitively as long as the simulation continues. The frequency was set at 20 min(-1) and the duration at 50% repolarization was 639 ms. The resting and overshoot potentials were -78 and +1.2 mV, respectively. The reconstructed pacemaker potentials closely matched those obtained from animal experiments. The model supports the idea that cyclic changes in [Ca2+]i and [IP3] play key roles in the generation of ICC pacemaker activity in the mouse small intestine.

Modeling of stochastic behavior of pacemaker potential in interstitial cells of Cajal

“…In ICCs, the channel was suggested to participate in the neurotransmitter-mediated depolarization rather than directly drives pacemaking (Kim et al, 2012). In our previous work (Youm et al, 2006), the simulated resting membrane potential seldom exceeded À78 mV which is more hyperpolarized than that of experimental recording (À71.5 mV). As the ICCs were found to have the Na þ -leak channel which could contribute to the slight depolarization of resting cell membrane, we formulated and incorporated it into our model as described in Appendix A.…”

“…This work is based on a previously published model (Youm et al, 2006) and further updated and newly employed components are described. All the components included in this updated model are schematically represented in Fig.…”

“…After the first biophysically based model of ICCs (Youm et al, 2006), several models with their own hypotheses have been developed. One of the model (Corrias and Buist, 2008) was based on the non-selective cation conductance (NSCC) hypothesis (Sanders et al, 2006).…”

Gastrointestinal system

“…Currently, there are three whole-cell biophysically based models specifically for simulating ICC pacemaker activity. The Youm et al 27. ICC model outlined seven ion conductances categorized into three ionic components (Ca 2+ , K + , and Na + ) and a series of intracellular Ca 2+ dynamics based on the Luo and Rudy25 (cardiac) approach to simulate intestinal pacemaker potentials.…”

Mitochondrial calcium handling within the interstitial cells of Cajal

“…A periodic structure represents the complex ER geometry, and, based on the estimated ratio of cytosolic to ER volumes, effective diffusion coefficients are computed (29). Estimates of ICC volume include 1,431 m 3 (81), and, combined with estimated MT and ER volumes of 13% and 10% of total, respectively (15), the cytosolic volume to ER volume ratio is 7.7. Only ER lumenal diffusive species have effective diffusion coefficients applied; all other diffusion coefficients are virtually identical across regions.…”