Abstract
Transgenic (TG) mice overexpressing β2-adrenergic receptors (β2-ARs) demonstrate enhanced myocardial function, which manifests in increased basal adenylyl cyclase activity, enhanced atrial contractility, and increased left ventricular function in vivo. To gain insights into the mechanisms of these effects, we developed a comprehensive mathematical model of the mouse ventricular myocyte overexpressing β2-ARs. We found that most of the β2-ARs are active in control conditions in TG mice. The simulations describe the dynamics of major signaling molecules in different subcellular compartments, increased basal adenylyl cyclase activity, modifications of action potential shape and duration, and the effects on L-type Ca2+ current and intracellular Ca2+ concentration ([Ca2+]i) transients upon stimulation of β2-ARs in control, after the application of pertussis toxin, upon stimulation with a specific β2-AR agonist zinterol, and upon stimulation with zinterol in the presence of pertussis toxin. The model also describes the effects of the β2-AR inverse agonist ICI-118,551 on adenylyl cyclase activity, action potential, and [Ca2+]i transients. The simulation results were compared with experimental data obtained in ventricular myocytes from TG mice overexpressing β2-ARs and with simulation data on wild-type mice. In conclusion, a new comprehensive mathematical model was developed that describes multiple experimental data on TG mice overexpressing β2-ARs and can be used to test numerous hypotheses. As an example, using the developed model, we proved the hypothesis of the major contribution of L-type Ca2+ current to the changes in the action potential and [Ca2+]i transient upon stimulation of β2-ARs with zinterol. NEW & NOTEWORTHY We developed a new mathematical model for transgenic mouse ventricular myocytes overexpressing β2-adrenoceptors that describes the experimental findings in transgenic mice. The model reveals mechanisms of the differential effects of stimulation of β2-adrenoceptors in wild-type and transgenic mice overexpressing β2-adrenoceptors.
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