Bulletin of Mathematical Biology

, Volume 76, Issue 6, pp 1352–1375

Modulation of the cAMP Response by G\(\alpha _i\) and G\(\beta \gamma \): A Computational Study of G Protein Signaling in Immune Cells

Original Article

DOI: 10.1007/s11538-014-9964-4

Cite this article as:
Leander, R. & Friedman, A. Bull Math Biol (2014) 76: 1352. doi:10.1007/s11538-014-9964-4
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Abstract

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.

Keywords

Mathematical modeling CAMP G proteins Immune cells 

Supplementary material

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Copyright information

© Society for Mathematical Biology 2014

Authors and Affiliations

  1. 1.Department of MathematicsMiddle Tennessee State UniversityMurfreesboroUSA
  2. 2.Department of MathematicsThe Ohio State UniversityColumbusUSA

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