Modeling cardiomyocyte signaling pathways

Cardiac cells have evolved elaborate signaling networks to support the coordinated response of the cell, organ, and ultimately organism to environmental stimuli, including physical and biochemical signals. Importantly, cardiac cell signaling pathways are tuned to respond across temporal and spatial scales to specific stimuli. Furthermore, dysregulation of cell signaling pathways is commonly observed in cardiovascular disease and arrhythmia. Quantitative analysis of cardiac cell signaling faces a number of unique challenges. The sheer number of constituent elements may pose a barrier to detailed characterization of the system (e.g. local concentrations and/or phosphorylation status/activity of kinases, target proteins) in vitro let alone in vivo. Furthermore, signaling pathways are often imbued with a degree of pleiotropy where the same network gives rise to multiple functional outputs. Adding to the complexity, signaling pathways tend to be highly nonlinear, lacking a well-defined beginning, middle and end. Together, the complex aspects of signaling provide both obstacles and exciting opportunities for mathematical modeling to generate a cohesive understanding of cardiac cell function. Despite these difficulties, mathematical modeling has been applied extensively to codify complex cell signaling networks across systems, including the heart. This chapter provides an introduction to the general approach for modeling cell signaling pathways followed by discussion of specific examples from efforts to understand the elaborate network of protein kinases and downstream targets which support the relatively rapid cardiac response to stress.