Key result
In silico modeling of rat ventricular myocytes predicted that adenylyl cyclase overexpression increases cAMP synthesis by 85% more than equivalent beta-1 receptor overexpression.
An in silico model of rat ventricular myocytes reveals that phosphorylation of L-type calcium channels and phospholamban is sufficient to predict dominant changes in beta-adrenergic-mediated contractility.
Rat myocyte model predictions warrant no clinical changes; leaves open whether adenylyl cyclase outperforms beta-1 receptor targeting in human heart failure.
The beta-adrenergic signaling pathway regulates cardiac myocyte contractility through a combination of feedforward and feedback mechanisms. We used systems analysis to investigate how the components and topology of this signaling network permit neurohormonal control of excitation-contraction coupling in the rat ventricular myocyte. A kinetic model integrating beta-adrenergic signaling with excitation-contraction coupling was formulated, and each subsystem was validated with independent biochemical and physiological measurements. Model analysis was used to investigate quantitatively the effects of specific molecular perturbations. 3-Fold overexpression of adenylyl cyclase in the model allowed an 85% higher rate of cyclic AMP synthesis than an equivalent overexpression of beta 1-adrenergic receptor, and manipulating the affinity of Gs alpha for adenylyl cyclase was a more potent regulator of cyclic AMP production. The model predicted that less than 40% of adenylyl cyclase molecules may be stimulated under maximal receptor activation, and an experimental protocol is suggested for validating this prediction. The model also predicted that the endogenous heat-stable protein kinase inhibitor may enhance basal cyclic AMP buffering by 68% and increasing the apparent Hill coefficient of protein kinase A activation from 1.0 to 2.0. Finally, phosphorylation of the L-type calcium channel and phospholamban were found sufficient to predict the dominant changes in myocyte contractility, including a 2.6x increase in systolic calcium (inotropy) and a 28% decrease in calcium half-relaxation time (lusitropy). By performing systems analysis, the consequences of molecular perturbations in the beta-adrenergic signaling network may be understood within the context of integrative cellular physiology.
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Saucerman et al. (2003) studied Cardiac myocyte contractility. In silico molecular perturbations (e.g., adenylyl cyclase overexpression) vs. Equivalent beta 1-adrenergic receptor overexpression / basal state was evaluated on Cyclic AMP synthesis and myocyte contractility. In silico modeling of rat ventricular myocytes predicted that adenylyl cyclase overexpression increases cAMP synthesis by 85% more than equivalent beta-1 receptor overexpression.
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