title: Modeling CaMKII in cardiac physiology: from molecule to tissue.
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 Ca(2+)/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.
authors.affiliation: The Dorothy M. Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University Columbus, OH, USA ; Department of Biomedical Engineering, College of Engineering, The Ohio State University Columbus, OH, USA.
authors.forename: Birce
authors.initials: B
authors.lastname: Onal
authors.affiliation: The Dorothy M. Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University Columbus, OH, USA.
authors.forename: Sathya D
authors.initials: SD
authors.lastname: Unudurthi
authors.affiliation: The Dorothy M. Davis Heart and Lung Research Institute, Wexner Medical Center, The Ohio State University Columbus, OH, USA ; Department of Biomedical Engineering, College of Engineering, The Ohio State University Columbus, OH, USA ; Department of Internal Medicine, Wexner Medical Center, The Ohio State University Columbus, OH, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hund
keywords: arrhythmias; calcium; calmodulin kinase II; heart failure; mathematical modeling