A Mathematical Model of the Combined β1- and β2-Adrenergic Signaling System in the Mouse Ventricular Myocyte

The β1- and β2-adrenergic signaling systems play different roles in the functioning of cardiac cells. Experimental data shows that the activation of the β1-adrenergic signaling system produces significant inotropic, lusitropic, and chronotropic effects in the heart, while the effects of the β2-adrenergic signaling system is less apparent. In this dissertation, a comprehensive experimentally-based mathematical model of the combined β1- and β2-adrenergic signaling systems in mouse ventricular myocytes is developed to simulate the experimental findings and make testable predictions of the behavior of the cardiac cells under different physiological conditions. Simulations describe the dynamics of major signaling molecules in different subcellular compartments; kinetics and magnitudes of phosphorylation of ion channels, transporters, and Ca2+ handling proteins; modifications of action potential shape and duration; and [Ca2+]i and [Na+]i dynamics upon stimulation of β1- and β2-adrenergic receptors (β1- and β2-ARs). The model reveals physiological conditions when β2-ARs do not produce significant physiological effects and when their effects can be measured experimentally. Simulations demonstrated that stimulation of β2-ARs with isoproterenol caused a marked increase in the magnitude of the L-type Ca2+ current, [Ca2+]i transient, and phosphorylation of phospholamban only upon additional application of pertussis toxin (PTX) or inhibition of phosphodiesterases of type 3 and 4. The model also made testable predictions of the changes in magnitudes of [Ca2+]i and [Na+]i fluxes, the rate of decay of [Na+]i concentration upon both combined and separate stimulation of β1- and β2-ARs, and the contribution of phosphorylation of PKA targets to the changes in the action potential and [Ca2+]i transient. A comprehensive mathematical model of the mouse ventricular myocyte overexpressing β2-adrenergic receptors was also developed. It was found that most of the β2-adrenergic receptors are active in control conditions in TG mice. Simulations describe the increased basal adenylyl cyclase activity; modifications of action potential; the effects on the L-type Ca2+ current and [Ca2+]i transients upon stimulation of β2-adrenergic receptors in control, after the application of PTX, upon stimulation with zinterol, and upon stimulation with zinterol in the presence of PTX. The model also describes the effects of inverse agonist ICI-118,551 on adenylyl cyclase activity, action potential, and [Ca2+]i transients