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Genetically modified mice are popular experimental models for studying the molecular bases and mechanisms of cardiac arrhythmia. A postgenome challenge is to classify the functional roles of genes in cardiac function. To unveil the functional role of various genetic isoforms of ion channels in generating cardiac pacemaking action potentials (APs), a mathematical model for spontaneous APs of mouse sinoatrial node (SAN) cells was developed. The model takes into account the biophysical properties of membrane ionic currents and intracellular mechanisms contributing to spontaneous mouse SAN APs. The model was validated by its ability to reproduce the physiological exceptionally short APs and high pacing rates of mouse SAN cells. The functional roles of individual membrane currents were evaluated by blocking their coding channels. The roles of intracellular Ca(2+)-handling mechanisms on cardiac pacemaking were also investigated in the model. The robustness of model pacemaking behavior was evaluated by means of one- and two-parameter analyses in wide parameter value ranges. This model provides a predictive tool for cellular level outcomes of electrophysiological experiments. It forms the basis for future model development and further studies into complex pacemaking mechanisms as more quantitative experimental data become available.

Original publication

DOI

10.1152/ajpheart.00143.2010

Type

Journal article

Journal

Am J Physiol Heart Circ Physiol

Publication Date

09/2011

Volume

301

Pages

H945 - H963

Keywords

Action Potentials, Animals, Arrhythmias, Cardiac, Biological Clocks, Calcium Channels, Calcium Signaling, Computer Simulation, Genetic Predisposition to Disease, Homeostasis, Ion Channels, Ion Transport, Kinetics, Mice, Mice, Transgenic, Models, Cardiovascular, Numerical Analysis, Computer-Assisted, Potassium, Potassium Channels, Sinoatrial Node, Sodium, Sodium Channels