Strange bedfellows: biologists and mathematical modelers tie the knot on cardiomyocyte calcium homeostasis

摘要

The past several decades of experimental investigation have revealed a rich complexity of cardiomyocyte Ca2+ dynamics. Integrating and decomposing these complex data now increasingly relies on mathematical modeling approaches. In reviewing the evolution and contributions of these cardiomyocyte models, we emphasize the importance of data-driven model parameterization, with iterative data exchange between experimentalists and modelers leading to novel generation of hypotheses. Introduction In the simplest paradigm of cardiomyocyte Ca2+ homeostasis, L-type Ca2+ channels (LCCs) are opened during the depolarizing action potential, and the resulting Ca2+ influx triggers release of Ca2+ from the sarcoplasmic reticulum (SR) via ryanodine receptors (RyRs). Following release, Ca2+ is recycled into the SR by the SR Ca2+ ATPase (SERCA), and extruded from the cell, primarily by the Na+-Ca2+ exchanger (NCX). The action potential plays a key role in regulating the Ca2+ transient through its effects on the magnitude and kinetics of LCC and NCX currents. However, these currents themselves also regulate action potential shape, as do various Na+ and K+ currents. As we have increasingly studied the details of this interconnected system of pumps, channels and exchangers it has become clear that the complexity of cardiac Ca2+ dynamics is beyond intuitive analysis. Indeed, in many instances experimental analysis now relies on the use of quantitative models to integrate data and reveal mechanisms. In this review, we outline developments in modeling cardiomyocyte Ca2+ homeostasis, and highlight the need for an iterative loop formed between experiment and model. We particularly emphasize the advantages of data-driven model parameterization, and provide examples where the failure of models to reproduce experimental data has led to novel hypothesis generation later validated in experiments.