Fig. 8.

Gαs-PKA pathway signalopathy pathophysiology. (A) Pathophysiology of cholera. Cholera is an intestinal parasite that enters the digestive tract when consumed via contaminated water. In the intestinal epithelium, cholera toxin ADP-ribosylates and activates Gαs, leading to overactivation of PKA. PKA directly phosphorylates the CFTR to facilitate channel opening. Efflux of chloride ions disrupts normal ionic gradients, and water passes into the intestinal lumen to compensate. Consequently, the clinical manifestations of cholera include watery diarrhea and dehydration. (B) Cushing syndrome pathophysiology. ACTH is secreted by the pituitary gland in the brain and travels through the bloodstream to the adrenal gland located on top of the kidney. ACTH binds to the melanocortin receptor (MC₂R) on the surface of adrenocortical cells to activate PKA and stimulate cortisol secretion. In Cushing syndrome, loss-of-function mutation in RIα (or gain-of-function mutation in Cα) leads to persistent PKA activation and excess cortisol secretion. Clinical manifestations of the disease exacerbate the effects of cortisol and include hypertension, hyperglycemia, and obesity. (C) Fibrous dysplasia pathophysiology. Fibrous dysplasia is a postzygotic disease caused by activating mutation in GNAS. Persistent activation of PKA in mesenchymal stem cells impairs proper differentiation to adipocyte, chondrocyte, and osteogenic lineages. In particular, accumulation of osteogenic precursors shifts the balance of osteoblasts and osteoclasts to favor bone resorption by osteoclasts. Resulting clinical manifestation of the disease includes brittle bone and frequent fracture or deformity.