A Compartmentalized Mathematical Model of the b1-Adrenergic Signaling System in Mouse Ventricular

The b1-adrenergic signaling system plays an important role in the functioning of cardiac cells. Experimental data shows that the activation of this system produces inotropy, lusitropy, and chronotropy in the heart, such as increased magnitude and relaxation rates of [Ca2+]i transients and contraction force, and increased heart rhythm. However, excessive stimulation of b1-adrenergic receptors leads to heart dysfunction and heart failure. In this paper, a comprehensive, experimentally based mathematical model of the b1-adrenergic signaling system for mouse ventricular myocytes is developed, which includes major subcellular functional compartments (caveolae, extracaveolae, and cytosol). The model describes biochemical reactions that occur during stimulation of b1-adrenoceptors, changes in ionic currents, and modifications of Ca 2+ handling system. Simulations describe the dynamics of major signaling molecules, such as cyclic AMP and protein kinase A, in different subcellular compartments; the effects of inhibition of phosphodiesterases on cAMP production; kinetics and magnitudes of phosphorylation of ion channels, transporters, and Ca2+ handling proteins; modifications of action potential shape and duration; magnitudes and relaxation rates of [Ca2+]i transients; changes in intracellular and transmembrane Ca 2+ fluxes; and [Na+]i fluxes and dynamics. The model elucidates complex interactions of ionic currents upon activation of b1