Distinct physiological effects of beta 1-and beta 2-adrenoceptors in mouse ventricular myocytes: insights from a compartmentalized mathematical model

作者：Rozier Kelvin; Bondarenko Vladimir E^*

来源：American Journal of Physiology - Cell Physiology, 2017, 312(5): C595-C623.

DOI：10.1152/ajpcell.00273.2016

• cardiac action potential
• calcium dynamics
• isoproterenol
• signaling systems
• sodium dynamics

The beta(1)- and beta(2)-adrenergic signaling systems play different roles in the functioning of cardiac cells. Experimental data show that the activation of the beta(1)-adrenergic signaling system produces significant inotropic, lusitropic, and chronotropic effects in the heart, whereas the effects of the beta(2)-adrenergic signaling system is less apparent. In this paper, a comprehensive compartmentalized experimentally based mathematical model of the combined beta(1)- and beta(2)-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 beta(1)- and beta 2-adrenergic receptors (beta(1)- and beta(2)-ARs). The model reveals physiological conditions when beta(2)-ARs do not produce significant physiological effects and when their effects can be measured experimentally. Simulations demonstrated that stimulation of beta(2)-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 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 beta(1)- and beta(2)-ARs, and the contribution of phosphorylation of PKA targets to the changes in the action potential and [Ca2+](i) transient.

• 出版日期2017-5-1