Modulation of the cAMP Response by Galpha _i and Gbeta gamma : A Computational Study of G Protein Signaling in Immune Cells

Cyclic AMP is important for the resolution of inflammation, as it promotes anti-inflammatory signaling in several immune cell lines. In this paper, we present an immune cell specific model of the cAMP signaling cascade, paying close attention to the specific isoforms of adenylyl cyclase (AC) and phosphodiesterase that control cAMP production and degradation, respectively, in these cells. The model describes the role that G protein subunits, including G (alpha _s) , G (alpha _i) , and G (beta gamma ) , have in regulating cAMP production. Previously, G (alpha _i) activation has been shown to increase the level of cAMP in certain immune cell types. This increase in cAMP is thought to be mediated by (beta gamma ) subunits which are released upon G (alpha ) activation and can directly stimulate specific isoforms of AC. We conduct numerical experiments in order to explore the mechanisms through which G (alpha _i) activation can increase cAMP production. An important conclusion of our analysis is that the relative abundance of different G protein subunits is an essential determinant of the cAMP profile in immune cells. In particular, our model predicts that limited availability of (beta gamma ) subunits may both ((i)) enable immune cells to link inflammatory G (alpha _i) signaling to anti-inflammatory cAMP production thereby creating a balanced immune response to stimulation with low concentrations of PGE2, and ((ii)) prohibit robust anti-inflammatory cAMP signaling in response to stimulation with high concentrations of PGE2.