Modeling β-Adrenergic Control of Cardiac Myocyte Contractility in Silico

• Published in: The Journal of biological chemistry Vol. 278; no. 48; p. 47997
• Main Authors: Jeffrey J. Saucerman, Laurence L. Brunton, Anushka P. Michailova, Andrew D. McCulloch
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 28-11-2003
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M308362200

The β-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 β-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 β 1 -adrenergic receptor, and manipulating the affinity of G s α 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 2.6× 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 β-adrenergic signaling network
may be understood within the context of integrative cellular physiology.