Modeling species-specific diacylglycerol dynamics in the RAW 264.7 macrophage.
A mathematical model of the G protein signaling pathway in RAW 264.7 macrophages downstream of P2Y(6) 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.
Callender
Hannah L
HL
Department of Mathematics, Vanderbilt University, 1326 Stevenson Center, Nashville, TN 37240, USA. callende@up.edu
Horn
Mary Ann
MA
DeCamp
Dianne L
DL
Sternweis
Paul C
PC
Alex Brown
H
H
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003198:Computer Simulation; D003600:Cytosol / Q000378:metabolism; D004075:Diglycerides / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006868:Hydrolysis; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D008962:Models, Theoretical; D010766:Phosphorylation; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D015398:Signal Transduction; D014530:Uridine Diphosphate / Q000737:chemistry
D004075:Diglycerides; D018048:Receptors, Purinergic P2; C099845:purinoceptor P2Y6; D014530:Uridine Diphosphate; D019204:GTP-Binding Proteins; D002118:Calcium