Cyclic adenosine monophosphate signaling pathway via Gs protein (cAMP/Gs pathway)

The cAMP signaling pathway via Gs protein is a ubiquitous intracellular cascade that converts extracellular signals into physiological responses (Source: StatPearls, Physiology, Adenosine Monophosphate, 2023). It is triggered by the binding of ligands to Gs-coupled G protein-coupled receptors (GPCRs), which activates the stimulatory G protein (Gs) (Source: NIH, G protein-coupled receptors, 2022). The Gs alpha subunit then stimulates adenylyl cyclase to produce cyclic adenosine monophosphate (cAMP) from ATP (Source: UniProt, G protein subunit alpha S, P63092). As a second messenger, cAMP activates Protein Kinase A (PKA) and Exchange Proteins Directly Activated by cAMP (EPAC), leading to the phosphorylation of various target proteins and the regulation of gene expression via CREB (Source: PubMed, cAMP signaling in health and disease, 2017). This pathway is essential for regulating heart rate, smooth muscle relaxation, and endocrine secretion. Dysregulation of the pathway is linked to diseases such as McCune-Albright syndrome, pituitary tumors, and heart failure (Source: NIH, McCune-Albright syndrome, GARD). Pharmacological modulation is achieved through GPCR agonists/antagonists, adenylyl cyclase activators like forskolin, or phosphodiesterase inhibitors that prevent cAMP degradation.

Other names

Gs-adenylyl cyclase-cAMP pathwayGs-coupled receptor signalingStimulatory G protein signaling cascadeGs-mediated cAMP signaling

Ligand binding to Gs-coupled GPCRs induces a conformational change that activates the Gs protein, causing the alpha subunit (Galpha-s) to exchange GDP for GTP. The activated Galpha-s dissociates and stimulates adenylyl cyclase, increasing intracellular cAMP levels. cAMP then binds to the regulatory subunits of Protein Kinase A (PKA), releasing active catalytic subunits that phosphorylate target proteins, and also activates EPAC proteins to regulate various cellular processes.