Abstract
Post-translational modification of membrane proteins (e.g., ion channels, receptors) by protein kinases is an essential mechanism for control of excitable cell function. Importantly, loss of temporal and/or spatial control of ion channel post-translational modification is common in congenital and acquired forms of cardiac disease and arrhythmia. The multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) regulates a number of diverse cellular functions in heart, including excitation-contraction coupling, gene transcription, and apoptosis. Dysregulation of CaMKII signaling has been implicated in human and animal models of disease. Understanding of CaMKII function has been advanced by mathematical modeling approaches well-suited to the study of complex biological systems. Early kinetic models of CaMKII function in the brain characterized this holoenzyme as a bistable molecular switch capable of storing information over a long period of time. Models of CaMKII activity have been incorporated into models of the cell and tissue (particularly in the heart) to predict the role of CaMKII in regulating organ function. Disease models that incorporate CaMKII overexpression clearly demonstrate a link between its excessive activity and arrhythmias associated with congenital and acquired heart disease. This review aims at discussing systems biology approaches that have been applied to analyze CaMKII signaling from the single molecule to intact cardiac tissue. In particular, efforts to use computational biology to provide new insight into cardiac disease mechanisms are emphasized.
Highlights
Signal transduction, whereby a cell receives and processes extracellular information to coordinate a cellular process, is critical for normal cell function
Systems biology and computational modeling of biological systems have become increasingly valuable in enhancing our understanding of these complex protein interaction networks
Systems biology involves the study of the complex interactions and associated dynamics found in biological systems
Summary
Whereby a cell receives and processes extracellular information to coordinate a cellular process, is critical for normal cell function. As systems-based approaches have gained favor in the study of human disease processes, so has mathematical modeling of biological systems with associated advancements in understanding complex biological phenomenon like circadian rhythms, apoptosis, synaptic plasticity, and cell communication (Herzel and Bluthgen, 2008; Kotaleski and Blackwell, 2010). CaMKII serves as a nodal point for a vast signaling network that regulates critical processes like learning and memory, cardiomyocyte contractility, T-cell selection, and expression and localization of class II MHC molecules in dendritic cells (Braun and Schulman, 1995; Maier and Bers, 2002; McGargill et al, 2005; Herrmann et al, 2007; Anderson et al, 2011; Swaminathan et al, 2012). Current research aims at elucidating how this large effector molecule acts as a pro-cardiac disease/arrhythmogenic www.frontiersin.org
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