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Biophys. J. BioFAST: First Published May 4, 2007. doi:10.1529/biophysj.106.097469
© 2007 by the Biophysical Society.

A more recent version of this article appeared on August 1, 2007.
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BIOPHYSICAL THEORY AND MODELING

A Kinetic Model for Calcium Dynamics in RAW 264.7 Cells: 1. Mechanisms, Parameters and Sub-populational Variability

Mano Ram Maurya 1 and Shankar Subramaniam 2*

1 University of California, San Diego
2 University of California at San Diego Depts. of Bioengineering & Chemistry &

* To whom correspondence should be addressed. E-mail: shankar{at}ucsd.edu.

Submitted on September 13, 2006
Revised on November 13, 2006
Accepted on 27 February 2007


  Abstract
Calcium (Ca2+) is an important second messenger and has been the subject of numerous experimental measurements and mechanistic studies in intracellular signaling. Calcium profile can also serve as a useful cellular phenotype. Kinetic models of calcium dynamics provide quantitative insights into the calcium signaling networks. We report here, the development of a complex kinetic model for calcium dynamics in RAW 264.7 cells stimulated by the C5a ligand. The model is developed using the vast number of measurements of in vivo calcium dynamics carried out in the Alliance for Cellular Signaling (AfCS) Laboratories. Ligand binding, phospholipase C-beta (PLC-beta) activation, inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) dynamics and calcium exchange with mitochondria and extracellular matrix have all been incorporated into the model. The experimental data include both data from native and knockdown cell lines. Sub-populational variability in measurements is addressed by allowing non-kinetic parameters to vary across datasets. The model predicts temporal response of Ca2+ concentration for various doses of C5a under different initial conditions. The optimized parameters for IP3R dynamics are in agreement with the legacy data. Further, the half-maximal effect concentration (EC50) of C5a and the predicted dose response are comparable to those seen in AfCS measurements. Sensitivity analysis shows that the model is robust to parametric perturbations.

Key Words: complement 5a, in-vivo knockdown data in RAW 264.7 cells, inositol 1,4,5-trisphosphate, intracellular calcium signaling, kinetic modeling, parameter optimization and sensitivity analysis, subpopulational variability






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Copyright © 2007 by the Biophysical Society.