Georgia Institute of Technology College of Sciences

A comprehensive mathematical model of β1-adrenergic signaling system for mouse ventricular myocytes is developed. The model myocyte consists of three major compartments (caveolae, extracaveolae, and cytosol) and includes several modules that describe biochemical reactions and electrical activity upon the activation of β1-adrenergic receptors. In the model, β1-adrenergic receptors are stimulated by an agonist isoproterenol, which leads to activation of Gs-protein signaling pathway to a different degree in different compartments. Gs-protein, in turn, activates adenylyl cyclases to produce cyclic AMP and to activate protein kinase A. Catalytic subunit of protein kinase A phosphorylates cardiac ion channels and intracellular proteins that regulate Ca2+ dynamics. Phosphorylation is removed by the protein phosphatases 1 and 2A. The model is extensively verified by the experimental data on β1-adrenergic regulation of cardiac function. It reproduces time behavior of a number of biochemical reactions and voltage-clamp data on ionic currents in mouse ventricular myocytes; β1-adrenergic regulation of the action potential and intracellular Ca2+ transients; and calcium and sodium fluxes during action potentials. The model also elucidates the mechanism of action potential prolongation and increase in intracellular Ca2+ transients upon stimulation of β1-adrenergic receptors.