Cyclic Adenosine Monophosphate in Cardiac and Sympathoadrenal GLP-1 Receptor Signaling: Focus on Anti-Inflammatory Effects

Abstract

Glucagon-like peptide-1 (GLP-1) is a multifunctional incretin hormone with various physiological effects beyond its well-characterized effect of stimulating glucose-dependent insulin secretion in the pancreas. An emerging role for GLP-1 and its receptor, GLP-1R, in brain neuroprotection and in the suppression of inflammation, has been documented in recent years. GLP-1R is a G protein-coupled receptor (GPCR) that couples to Gs proteins that stimulate the production of the second messenger cyclic 3’,5’-adenosine monophosphate (cAMP). cAMP, acting through its two main effectors, protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac), exerts several anti-inflammatory (and some pro-inflammatory) effects in cells, depending on the cell type. The present review discusses the cAMP-dependent molecular signaling pathways elicited by the GLP-1R in cardiomyocytes, cardiac fibroblasts, central neurons, and even in adrenal chromaffin cells, with a particular focus on those that lead to anti-inflammatory effects by the GLP-1R. Fully elucidating the role cAMP plays in GLP-1R’s anti-inflammatory properties can lead to new and more precise targets for drug development and/or provide the foundation for novel therapeutic combinations of the GLP-1R agonist medications currently on the market with other classes of drugs for additive anti-inflammatory effect.