Figure 2: Simplified cartoon of Gs-dependent regulatory cascades in pancreatic cancer cells and their normal epithelial precursor cells. Activated Adenylyl Cyclase (AC) increases intracellular cAMP and activated PKA, which activate the EGFR pathway via transactivation and release of EGF and amphiregulin while at the same time increasing the production of Vascular Endothelial Growth Factor (VEGF) and arachidonic acid (AA). COX-2 inhibitors reduce Gs-signaling by blocking the Gs-coupled receptors (EP2 and EP4) for prostaglandin E2 while beta-blockers inhibit Gs-signaling coupled to beta-adrenergic receptors (β-ARs). GABA inhibits signaling downstream of all Gs-coupled receptors by binding to the Gi-coupled GABA-B receptors (GABAB- Rs) that inhibit the activation of AC. The β2-AR which is coupled to both, Gs and Gi, inhibits excessive AC-signaling via Gi activation. Receptors coupled to Gq, such as the α1-AR, can inhibit cAMP-dependent signaling by PKC-induced inhibition of PKA activation.