Modelling sarcoplasmic reticulum calcium ATPase and its regulation in cardiac myocytes

Abstract

When developing large-scale mathematical models of physiology, some reduction in complexity is necessarily required to maintain computational efficiency. A prime example of such an intricate cell is the cardiac myocyte. For the predictive power of the cardiomyocyte models, it is vital to accurately describe the calcium transport mechanisms, since they essentially link the electrical activation to contractility. The removal of calcium from the cytoplasm takes place mainly by the Na C /Ca 2C exchanger, and the sarcoplasmic reticulum Ca 2C ATPase (SERCA). In the present study, we review the properties of SERCA, its frequency-dependent and b-adrenergic regulation, and the approaches of mathematical modelling that have been used to investigate its function. Furthermore, we present novel theoretical considerations that might prove useful for the elucidation of the role of SERCA in cardiac function, achieving a reduction in model complexity, but at the same time retaining the central aspects of its function. Our results indicate that to faithfully predict the physiological properties of SERCA, we should take into account the calcium-buffering effect and reversible function of the pump. This 'uncomplicated' modelling approach could be useful to other similar transport mechanisms as well.

Compartment calcium model of frog skeletal muscle during activation

“…Current experimental data supports the theory that a single conformational change of the pump allows the movement of Ca 2 þ across the membrane and into the SR (Berchtold et al, 2000;Salviati et al, 1984). We use a standard Hill type equation to model the SERCA, as in other modeling studies, assuming that the pumping rate can saturate and that it is first order (Hill coefficient of 1, Cannell and Allen, 1984;Holly and Poledna, 1989;Koivumaki et al, 2009). The parameters for SERCA include a maximal pumping rate V max (μM ms À 1 ) and dissociation constant K MS (μM).…”

Calcium Channel Blockade in Embryonic Cardiac Progenitor Cells Disrupts Normal Cardiac Cell Differentiation

“…In recent years research on ionic currents in the embryonic mammalian heart has related to studies of differentiated cardiomyocytes of the tubular or 4-chambered heart or of differentiated ventricular cells in culture [2,16,17]. Many studies have been directed at Ca handling and ion channels in hESC-derived cardiomyocytes [1,3,18,19].…”

Translating Intracellular Calcium Signaling into Models

“…However, experimental measurements strongly suggest that firstly luminal Ca 2+ feeds back to SERCA pump dynamics and secondly Ca 2+ movement between the cytosol and the ER/SR proceeds along multiple distinct states of the SERCA pump molecule. These experimental results have led to more comprehensive models of SERCA pumps such as in (Sneyd et al 2003;Shannon et al 2004;Higgins et al 2006;Koivumäki et al 2009;Tran et al 2009) The advantage of compartmentalized models lies in the computational ease in accounting for largely varying Ca 2+ concentrations and spatial gradients. A single point model cannot incorporate the different peak values and time courses of e.g.…”