BIOPHYSICAL THEORY AND MODELING |
A Kinetic Model for Calcium Dynamics in RAW 264.7 Cells: 2. Knockdown Response and Long-Term Response
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
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Abstract |
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This paper addresses how quantitative models as the one proposed in the companion paper can be used to study cellular network perturbations such as knockdowns and pharmacological perturbations in a predictive manner. Using the kinetic model for cytosolic calcium dynamics in RAW 264.7 cells developed in the companion paper, calcium response to complement 5a (C5a) for the knockdown of seven proteins (C5a receptor; G-beta-2; G-alpha,i-2,3; regulator of G-protein signaling (RGS)-10; G-protein coupled receptor kinase (GRK)-2; phospholipase C (PLC) beta-3; Arrestin) is predicted and validated against the data from the Alliance for Cellular Signaling (AfCS). The knockdown responses provide insights into how altered expressions of important proteins in disease states result in intermediate measurable phenotypes. Long-term response and long-term dose response have also been predicted providing insights into how the receptor desensitization, internalization and recycle result in tolerance. Sensitivity analysis of long-term response shows that the mechanisms and parameters in the receptor recycle path are important for long-time calcium dynamics.
Key Words:
complement 5a, inositol 1,4,5-trisphosphate, intracellular calcium signaling, kinetic modeling, knockdown perturbation and sensitivity analysis, receptor internalization, recovery and long-term response
