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

Youm, Jae Boum; Leem, Chae Hun; Lee, Sung Ryul; Song, In-Sung; Kim, Hyoung Kyu; Heo, Hye Jin; Kim, Byung Joo; Kim, Nari; Han, Jin

doi:10.1016/j.pbiomolbio.2014.09.002

Cited by 7 publications

(8 citation statements)

References 63 publications

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“…The first biophysically based model of ICC reproduced spontaneous generation of pacemaker potentials (20). Although the model was able to reproduce some of the characteristic features of pacemaker potentials in mouse intestinal ICC, Ano1 channels were not included in this model.…”

Section: Introductionmentioning

confidence: 99%

Na-K-2Cl Cotransporter and Store-Operated Ca2+ Entry in Pacemaking by Interstitial Cells of Cajal

Youm

Zheng

Koh

et al. 2019

Biophysical Journal

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Pacemaker depolarization in interstitial cells of Cajal (ICCs) is believed to be induced by Ca 2þ transients and activation of anoctamin-1 (Ano1) channels in the plasma membrane. However, block of store-operated calcium entry (SOCE) or the Na-K-2Cl cotransporter (NKCC1) terminates pacemaker activity in ICC, indicating these transporters are involved in the initiation or maintenance of pacemaker activity. We hypothesized that SOCE contributes to pacemaker depolarization by maintaining [Ca 2þ ] in the endoplasmic reticulum, which is the underlying source of Ca 2þ transients for activation of Ano1. NKCC1 maintains the Cl À gradient supporting the driving force for inward current mediated by Ano1. Currently mechanisms sustaining release of Ca 2þ and activation of Ano1 channels during the plateau phase of slow waves are unknown, but the reverse mode of the Na þ / Ca 2þ exchange may contribute. We generated a mathematical model of pacemaker activity based on current empirical observations from ICC of mouse small intestine that incorporates functions of SOCE and NKCC1. This model reproduces experimental findings, suggesting roles for SOCE and Ano1 channels: blocking of either NKCC1 or SOCE in our model terminates pacemaker activity. Direct contribution of NKCC1 to pacemaker activity in a beat-to-beat manner is not predicted by our model. Instead, NKCC1 plays a maintenance role supporting the driving force for Cl À efflux. Incorporation of SOCE allows the model to drive pacemaker activity without a diastolic depolarization, as observed in cardiac pacemaking. Further biological experiments are necessary to validate and further refine the roles of NKCC1, Na þ /Ca 2þ exchange, and Ano1 in the pacemaker mechanism of ICC.

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Section: Introductionmentioning

confidence: 99%

Na-K-2Cl Cotransporter and Store-Operated Ca2+ Entry in Pacemaking by Interstitial Cells of Cajal

Youm

Zheng

Koh

et al. 2019

Biophysical Journal

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“…SAC is a type of mechanically activated ionic channels, exhibits direct modulations on action potentials of myocytes in a strain-dependent manner. In accordance with previous studies [16, 32, 33], I SAC is modelled using the following formulation: where G stretch and E stretch are the maximum conductance and reversal potential of the channel, respectively, and P m is the normalised open probability of I SAC , given by: …”

Section: Methodsmentioning

confidence: 99%

“…In this study, G stretch = 0.0061 ms/μF; E stretch = −1 mV [16]; ε half = 0.163 [32]; K ε = 0.0266. I SAC is assumed to be equally permeable to three major ions: sodium (Na + ), potassium (K + ), and calcium (Ca 2+ ).…”

Section: Methodsmentioning

confidence: 99%

“…Here, ε is the engineering strain (linearly dependent on the stretch), ε half is the half activation strain, and K ε is the activation slope. In this study, G stretch = 0.0061 ms/μF; E stretch = −1 mV [ 16 ]; ε half = 0.163 [ 32 ]; K ε = 0.0266. I SAC is assumed to be equally permeable to three major ions: sodium (Na + ), potassium (K + ), and calcium (Ca 2+ ).…”

Section: Methodsmentioning

confidence: 99%

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Electro-mechanical dynamics of spiral waves in a discrete 2D model of human atrial tissue

Brocklehurst

Zhang

et al. 2017

PLoS ONE

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We investigate the effect of mechano-electrical feedback and atrial fibrillation induced electrical remodelling (AFER) of cellular ion channel properties on the dynamics of spiral waves in a discrete 2D model of human atrial tissue. The tissue electro-mechanics are modelled using the discrete element method (DEM). Millions of bonded DEM particles form a network of coupled atrial cells representing 2D cardiac tissue, allowing simulations of the dynamic behaviour of electrical excitation waves and mechanical contraction in the tissue. In the tissue model, each cell is modelled by nine particles, accounting for the features of individual cellular geometry; and discrete inter-cellular spatial arrangement of cells is also considered. The electro-mechanical model of a human atrial single-cell was constructed by strongly coupling the electrophysiological model of Colman et al. to the mechanical myofilament model of Rice et al., with parameters modified based on experimental data. A stretch-activated channel was incorporated into the model to simulate the mechano-electrical feedback. In order to investigate the effect of mechano-electrical feedback on the dynamics of spiral waves, simulations of spiral waves were conducted in both the electromechanical model and the electrical-only model in normal and AFER conditions, to allow direct comparison of the results between the models. Dynamics of spiral waves were characterized by tracing their tip trajectories, stability, excitation frequencies and meandering range of tip trajectories. It was shown that the developed DEM method provides a stable and efficient model of human atrial tissue with considerations of the intrinsically discrete and anisotropic properties of the atrial tissue, which are challenges to handle in traditional continuum mechanics models. This study provides mechanistic insights into the complex behaviours of spiral waves and the genesis of atrial fibrillation by showing an important role of the mechano-electrical feedback in facilitating and promoting atrial fibrillation.

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“…GISTs account for 0.1-3% of all gastrointestinal malignancies (1). The ICCs in the muscularis propria and myenteric plexus are known as the pacemaker cells of the gastrointestinal tract (2). GISTs have been demonstrated to express the receptor tyrosine kinase protein cluster of differentiation (CD)117, also known as proto-oncogene c-Kit (3).…”

Section: Introductionmentioning

confidence: 99%

Primary extragastrointestinal stromal tumor of the pleura: A case report

Zhang

Liu

et al. 2016

Oncology Letters

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Abstract. Gastrointestinal stromal tumors (GISTs) are the most common type of mesenchymal tumor of the gastrointestinal tract. The stomach and small intestine are the most common sites of occurrence. GISTs are mesenchymal neoplasms originating from the interstitial cells of Cajal (ICCs), and are characterized by positivity for cluster of differentiation (CD) 117, also known as proto-oncogene c-Kit. While the majority of GISTs develop in the alimentary tract, in rare cases they may also be found in extragastrointestinal tissues. This type of GIST is known as an extragastrointestinal stromal tumor (EGIST). Despite the fact that EGISTs have been reported in the mesentery, omentum and retroperitoneum, primary intrathoracic EGISTs, arising from the pleura or lungs, are rare. The patient presented in the current study was a 40-year-old man, who presented with a cough and pyrexia, with pleural effusion on the left side. Multiple nodules throughout the parietal pleura were identified by thoracoscopy and a diagnosis of primary GIST of pleura was established, since they were positive for CD117 and discovered on GIST-1 and there was no evidence of gastrointestinal tumors. Subsequently, the patient was administered with imatinib and had no signs of disease recurrence 2 years later.

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

Cited by 7 publications

References 63 publications

Na-K-2Cl Cotransporter and Store-Operated Ca2+ Entry in Pacemaking by Interstitial Cells of Cajal

Na-K-2Cl Cotransporter and Store-Operated Ca2+ Entry in Pacemaking by Interstitial Cells of Cajal

Electro-mechanical dynamics of spiral waves in a discrete 2D model of human atrial tissue

Primary extragastrointestinal stromal tumor of the pleura: A case report

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