Distinct physiological effects of β₁- and β₂-adrenoceptors in mouse ventricular myocytes: insights from a compartmentalized mathematical model

Abstract

The β- and β-adrenergic signaling systems play different roles in the functioning of cardiac cells. Experimental data show that the activation of the β-adrenergic signaling system produces significant inotropic, lusitropic, and chronotropic effects in the heart, whereas the effects of the β-adrenergic signaling system is less apparent. In this paper, a comprehensive compartmentalized experimentally based mathematical model of the combined β- and β-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 Ca handling proteins; modifications of action potential shape and duration; and [Ca] and [Na] dynamics upon stimulation of β- and β-adrenergic receptors (β- and β-ARs). The model reveals physiological conditions when β-ARs do not produce significant physiological effects and when their effects can be measured experimentally. Simulations demonstrated that stimulation of β-ARs with isoproterenol caused a marked increase in the magnitude of the L-type Ca current, [Ca] 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 [Ca] and [Na] fluxes, the rate of decay of [Na] concentration upon both combined and separate stimulation of β- and β-ARs, and the contribution of phosphorylation of PKA targets to the changes in the action potential and [Ca] transient.

Mathematical Modeling Physiological Effects of the Overexpression of β2-Adrenoceptors in Mouse Ventricular Myocytes

“…It showed the primary role of ␤ 1 -ARs in the inotropic response to stimulation with the ␤ 1and ␤ 2 -AR agonist isoproterenol. The model also demonstrated that the response to ␤ 2 -AR stimulation was only notable with the application of PTX or upon inhibition of PDE3 and PDE4 (22). However, it is interesting whether our model can simulate the experimental data obtained from TG mice overexpressing ␤ 2 -ARs after modifications and whether the model can reveal different responses of WT and TG mice to ␤-adrenergic stimulation.…”

“…Our model for the combined ␤ 1 -and ␤ 2 -adrenergic signaling system in mouse ventricular myocytes was able to explain only experimental data on WT mice (22). It showed the primary role of ␤ 1 -ARs in the inotropic response to stimulation with the ␤ 1and ␤ 2 -AR agonist isoproterenol.…”

“…The mathematical model for TG mouse ventricular myocytes overexpressing ␤ 2-ARs was obtained from our previously published mathematical models of mouse ventricular myocytes (2,3,20), including a compartmentalized model of the combined ␤ 1-and ␤2-adrenergic signaling system (22). To minimize the number of intracellular compartments without the loss of significant functionality of the model, the model cell consists of three major compartments: 1) the caveolar compartment represents the subsarcolemmal space associated with the cholesterol-rich membrane domain that includes caveolin 3, 2) the extracaveolar compartment represents the subsarcolemmal space associated with cholesterol-rich lipid rafts that do not include caveolin, and 3) the cytosolic compartment represents the bulk cytoplasmic compartment that is associated with the remainder of the cell membrane (2,9,22). Transversal t-tubules are considered as a part of the sarcolemma with a similar distribution of the three compartments mentioned above.…”

“…Therefore, we developed and explored a compartmentalized mathematical model of ventricular myocytes from TG mice overexpressing ␤ 2 -ARs. The model is based on the previously developed mathematical model of the combined ␤ 1 -and ␤ 2adrenergic signaling system in mouse ventricular cells, which was extensively verified by experimental data (22). In the new model, we implemented differences in the model parameters between WT and TG mice overexpressing ␤ 2 -ARs and simulated different myocyte behavior found experimentally at baseline and upon stimulation of ␤ 2 -ARs.…”

The role of β-adrenergic system remodeling in human heart failure: A mechanistic investigation

“…Investigations about cAMP signaling have given rise to detailed mathematical models of the adrenergic pathways, including signaling compartmentation and the interaction J o u r n a l P r e -p r o o f with electrophysiological proteins [15][16][17]. Simulations including these models can improve mechanistic insight into HF pathophysiology, but investigations performed to date have generally focused on effects of electrical remodeling rather than on HFinduced alterations in the β-AR system.…”