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Modeling beta-adrenergic control of cardiac myocyte contractility in silico
- Source :
- The Journal of biological chemistry. 278(48)
- Publication Year :
- 2003
- Publisher :
- United States: NASA Center for Aerospace Information (CASI), 2003.
-
Abstract
- 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.
- Subjects :
- Life Sciences (General)
Subjects
Details
- Language :
- English
- ISSN :
- 00219258
- Volume :
- 278
- Issue :
- 48
- Database :
- NASA Technical Reports
- Journal :
- The Journal of biological chemistry
- Notes :
- 5 P50 HL53773-09, , P41 RR08605, , CA00216
- Publication Type :
- Report
- Accession number :
- edsnas.20040087525
- Document Type :
- Report
- Full Text :
- https://doi.org/10.1074/jbc.M308362200