Modelling Cl ⁻ homeostasis and volume regulation of the cardiac cell

Abstract

We aim at introducing a Cl- homeostasis to the cardiac ventricular cell model (Kyoto model), which includes the sarcomere shortening and the mitochondria oxidative phosphorylation. First, we examined mechanisms underlying the cell volume regulation in a simple model consisting of Na+/K+ pump, Na+-K+-2Cl- cotransporter 1 (NKCC1), cystic fibrosis transmembrane conductance regulator, volume-regulated Cl- channel and background Na+, K+ and Cl- currents. The high intracellular Cl- concentration of approximately 30 mM was achieved by the balance between the secondary active transport via NKCC1 and passive currents. Simulating responses to Na+/K+ pump inhibition revealed the essential role of Na+/K+ pump in maintaining the cellular osmolarity through creating the negative membrane potential, which extrudes Cl- from a cell, confirming the previous model study in the skeletal muscle. In addition, this model well reproduced the experimental data such as the responses to hypotonic shock in the presence or absence of beta-adrenergic stimulation. Finally, the volume regulation via Cl- homeostasis was successfully incorporated to the Kyoto model. The steady state was well established in the comprehensive cell model in respect to both the intracellular ion concentrations and the shape of the action potential, which are all in the physiological range. The source code of the model, which can reproduce every result, is available from http://www.sim-bio.org/.

Ionic Mechanisms Underlying the Positive Chronotropy Induced by β1-Adrenergic Stimulation in Guinea Pig Sinoatrial Node Cells: a Simulation Study

“…The ATP production rate was adjusted to obtain a steady state [ATP] of 7.0 mM, which was in the range of 5-10 mM [16] [17]. Second, the mechanisms of Cl -homeostasis and volume regulation [4,5] were incorporated by including ion flux via a Na + /K + /2Cl -cotransporter 1 (J NKCC1 ), background Cl -current (I Clb ), water flux, and LA. The magnitudes of I Clb and water flux were scaled according to the ratio of input capacitance between SANs and ventricular cells (Tables S4 and S9).…”

“…Using this model, we proposed the principal ionic mechanisms underlying the spontaneous action potential. In the current study, we revised the model by updating the ion channels and incorporating the mitochondria and β1-adrenergic cascade models described by Matsuoka et al (2004), Terashima et al (2006), Takeuchi et al (2006), and Kuzumoto et al (2007) [3][4][5][6] to analyze the roles of each target ion current, including the L-type Ca 2+ current (I CaL ), the sustained inward current (I st ), the hyperpolarizationactivated cation current (I ha ), and the slow component of the delayed rectifier K + current (I Ks ) in the positive chronotropy during β1-adrenergic stimulation. Our new model also includes an alteration of Ca 2+ dynamics during stimulation by calculating a modification of the Ca 2+ pump (SERCA) on the sarcoplasmic membrane.…”

Computation of Pump-Leak Flux Balance in Animal Cells

“…The overall ion traffic is described by a set of nonlinear and transcendental equations, which cannot be solved analytically. Numerical solutions of this problem have been developed in a series of studies [1,2,3,4,5,6,7,8,9,10]. Some of the published codes and executable files are available in a form that allows modification of kinetic parameters to some extent [7,10].…”

“…Numerical solutions of this problem have been developed in a series of studies [1,2,3,4,5,6,7,8,9,10]. Some of the published codes and executable files are available in a form that allows modification of kinetic parameters to some extent [7,10]. Nevertheless, further study in this direction seems to be necessary because the reported detailed computations have been optimized only for certain cell types, such as human red blood cells and reticulocytes [3,10], guinea-pig cardiomyocytes [7], or frog skeletal muscle [4,8].…”

A physiome standards-based model publication paradigm

“…A similar approach is to provide the model implementation in an applicationspecific format, such as ICELL (Demir 2006), LABHEART (Puglisi & Bers 2001) or SIMBIO Terashima et al 2006). While this approach allows significantly greater scope for annotation of the model implementation, depending on the capabilities of the software, users of such model implementations are restricted to the original application environment.…”