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

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 Gαs, Gαi, and Gβγ, have in regulating cAMP production. Previously, Gαi 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 βγ subunits which are released upon Gα activation and can directly stimulate specific isoforms of AC. We conduct numerical experiments in order to explore the mechanisms through which Gαi 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 βγ subunits may both (i) enable immune cells to link inflammatory Gαi 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.

Prostaglandin EP2 receptor: Novel therapeutic target for human cancers (Review)

“…cluster of differentiation (cd)4 + Th cells are a key effector in the adaptive immune system to control cancer (64) and the increase in cAMP is associated with a decrease in Th1 cells and IFN-γ (65). In addition, PGE2 can suppress the activities of natural killer cells and cytotoxic T lymphocytes, which are part of antitumor immunity (66).…”

Identification of novel genes in testicular cancer microenvironment based on ESTIMATE algorithm‐derived immune scores

“…This is consistent with a previous study conducted by Arumugham and Baldari (2017) that cAMP is a multifaceted modulator of immune synapse assembly and T cell activation, and which reveals that cAMP is involved in various kinds of the regulation of immune processes. Leander and Friedman (2014) found that cAMP played a critical role in the resolution of inflammation. Also, they revealed that cAMP can promote anti‐inflammatory signaling in several kinds of immune cells.…”

Cannabinoid Receptor 2 (CB2) Signals via G-alpha-s and Induces IL-6 and IL-10 Cytokine Secretion in Human Primary Leukocytes

“…However, balance between Gα and Gβγ subunit expression may determine overall cAMP responses 56 . As well, adenylyl cyclase isoforms can differ in their Gα sensitivities and expression levels can vary between immune cell types 55 .…”