A compartmentalized mathematical model of the β1-adrenergic signaling system in mouse ventricular myocytes successfully reproduced experimental data on cAMP dynamics, PKA activation, and L-type Ca2+ current modifications.
The b 1 -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 Ca 2+ i transients and contraction force, and increased heart rhythm. However, excessive stimulation of b 1 -adrenergic receptors leads to heart dysfunction and heart failure. In this paper, a comprehensive, experimentally based mathematical model of the b 1 -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 b 1 -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 Ca 2+ handling proteins; modifications of action potential shape and duration; magnitudes and relaxation rates of Ca 2+ 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 b 1adrenoceptors at different stimulation frequencies, which ultimately lead to a relatively modest increase in action potential duration and significant increase in Ca 2+ i transients. In particular, the model includes two subpopulations of the L-type Ca 2+ channels, in caveolae and extracaveolae compartments, and their effects on the action potential and Ca 2+ i transients are investigated. The presented model can be used by researchers for the interpretation of experimental data and for the developments of mathematical models for other species or for pathological conditions.
Vladimir E. Bondarenko (Fri,) conducted a other in None (Mathematical model of mouse ventricular myocytes). Simulated β1-adrenergic stimulation (Isoproterenol) vs. Simulated basal conditions was evaluated on Model validation against experimental data for cAMP, PKA, and Ca2+ dynamics. A compartmentalized mathematical model of the β1-adrenergic signaling system in mouse ventricular myocytes successfully reproduced experimental data on cAMP dynamics, PKA activation, and L-type Ca2+ current modifications.