TY - JOUR
T1 - Modeling species-specific diacylglycerol dynamics in the RAW 264.7 macrophage
AU - Callender, Hannah L.
AU - Horn, Mary Ann
AU - DeCamp, Dianne L.
AU - Sternweis, Paul C.
AU - Alex Brown, H.
N1 - Funding Information:
This work was supported by contributions from public and private sources, including the National Institutes of General Medicine Glue Grant Initiatives AfCS (U54 GM062114) and LIPID MAPS (U54 GM069338) http://www.lipidmaps.org . A complete listing of AfCS sponsors can be found at http://www.signaling-gateway.org/aboutus/sponsors.html . Dr. Horn's participation was supported by the National Science Foundation. Any opinion, findings, and conclusions or recommendations expressed are those of the authors and do not necessarily reflect the views of the NSF. We thank Glenn F. Webb for guidance in the theoretical mathematical analysis of the model. We also thank Jeffrey S. Forrester for early contributions, as well as Mark O. Byrne, Pavlina Ivanova, and David S. Myers for helpful discussions and suggestions.
PY - 2010/2
Y1 - 2010/2
N2 - A mathematical model of the G protein signaling pathway in RAW 264.7 macrophages downstream of P2Y6 receptors activated by the ubiquitous signaling nucleotide uridine 5'-diphosphate is developed. The model, which is based on time-course measurements of inositol trisphosphate, cytosolic calcium, and diacylglycerol, focuses particularly on differential dynamics of multiple chemical species of diacylglycerol. When using the canonical pathway representation, the model predicted that key interactions were missing from the current network structure. Indeed, the model suggested that accurate depiction of experimental observations required an additional branch to the signaling pathway. An intracellular pool of diacylglycerol is immediately phosphorylated upon stimulation of an extracellular receptor for uridine 5'-diphosphate and subsequently used to aid replenishment of phosphatidylinositol. As a result of sensitivity analysis of the model parameters, key predictions can be made regarding which of these parameters are the most sensitive to perturbations and are therefore most responsible for output uncertainty.
AB - A mathematical model of the G protein signaling pathway in RAW 264.7 macrophages downstream of P2Y6 receptors activated by the ubiquitous signaling nucleotide uridine 5'-diphosphate is developed. The model, which is based on time-course measurements of inositol trisphosphate, cytosolic calcium, and diacylglycerol, focuses particularly on differential dynamics of multiple chemical species of diacylglycerol. When using the canonical pathway representation, the model predicted that key interactions were missing from the current network structure. Indeed, the model suggested that accurate depiction of experimental observations required an additional branch to the signaling pathway. An intracellular pool of diacylglycerol is immediately phosphorylated upon stimulation of an extracellular receptor for uridine 5'-diphosphate and subsequently used to aid replenishment of phosphatidylinositol. As a result of sensitivity analysis of the model parameters, key predictions can be made regarding which of these parameters are the most sensitive to perturbations and are therefore most responsible for output uncertainty.
KW - Cellular signaling pathways
KW - Mathematical modeling
KW - P2Y receptor
KW - Sensitivity analysis
KW - Uridine 5'-diphosphate
UR - http://www.scopus.com/inward/record.url?scp=77649341997&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77649341997&partnerID=8YFLogxK
U2 - 10.1016/j.jtbi.2009.10.030
DO - 10.1016/j.jtbi.2009.10.030
M3 - Article
C2 - 19883664
AN - SCOPUS:77649341997
SN - 0022-5193
VL - 262
SP - 679
EP - 690
JO - Journal of Theoretical Biology
JF - Journal of Theoretical Biology
IS - 4
ER -