ABSTRACT:
This a model from the article:
Modeling beta-adrenergic control of cardiac myocyte contractility in silico.
Saucerman JJ, Brunton LL, Michailova AP, McCulloch AD. J Biol Chem
2003 Nov 28;278(48):47997-8003 12972422
,
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.
This model was taken from the CellML repository
and automatically converted to SBML.
The original model was:
Saucerman JJ, Brunton LL, Michailova AP, McCulloch AD. (2003) - version=1.0
The original CellML model was created by:
Geoffrey Nunns
gnunns1@jhu.edu
The University of Auckland
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Vijayalakshmi Chelliah 
