A Compartmentalized Model of the Beta1-Adrenergic Signaling System in Mouse Ventricular Myocytes

Abstract

The β1-adrenergic signaling system plays an important role in heart function. Activation of this system increases heart rhythm, heart contraction. It also increases blood flow throughout the body. However, in disease, stimulation of β1-adrenergic receptors can increase an occurrence of arrhythmias. Therefore, comprehensive experimental study and modeling of the β1-adrenergic signaling system in the heart is of significant importance. We developed an experimentally-based mathematical model of β1-adrenergic regulation of the action potential and Ca2+ dynamics in mouse ventricular myocytes. The model includes several modules that describe biochemical reactions, electrical activity, and protein phosphorylation during activation of β1-adrenergic receptors. The model cell consists of three major compartments: caveolae, extracaveolae, and cytosol. Concentrations of β1-adrenergic receptors, as well as other signaling molecules, vary across the different domains. In the model, β1-adrenergic receptors are stimulated by the catecholamine isoproterenol. This leads to the activation of the Gs-protein signaling pathway, which ultimately increases cyclic AMP concentration and activity of protein kinase A to different degrees in different domains. The catalytic subunit of protein kinase A phosphorylates ion channels and Ca2+ handling proteins, leading to an increase or decrease in their function. Dephosphorylation is performed by the protein phosphatases 1 and 2A. Our model reproduces time-dependent behavior of a number of biochemical reactions and voltage-clamp data on ionic currents in mouse ventricular myocytes. The model also predicts action potential prolongation as well as an increase in intracellular Ca2+ transients dependent upon stimulation of β1-adrenergic receptors. The accuracy of the model was tested against experimental findings.