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Modeling beta-adrenergic control of cardiac myocyte contractility in silicoThe 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.
Document ID
20040087525
Acquisition Source
Legacy CDMS
Document Type
Reprint (Version printed in journal)
External Source(s)
Authors
Saucerman, Jeffrey J.
(University of California San Diego, La Jolla, California 92093-0412, United States)
Brunton, Laurence L.
Michailova, Anushka P.
McCulloch, Andrew D.
McCullough, A. D.
Date Acquired
August 21, 2013
Publication Date
November 28, 2003
Publication Information
Publication: The Journal of biological chemistry
Volume: 278
Issue: 48
ISSN: 0021-9258
Subject Category
Life Sciences (General)
Funding Number(s)
CONTRACT_GRANT: 5 P50 HL53773-09
CONTRACT_GRANT: P41 RR08605
CONTRACT_GRANT: CA00216
Distribution Limits
Public
Copyright
Other
Keywords
Non-NASA Center
NASA Program Biomedical Research and Countermeasures
NASA Discipline Cardiopulmonary

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