Fig. 3.

Updated model of prolonged intracellular GPCR signaling based on live-cell imaging. In the traditional model of G protein-coupled receptor (GPCR) signaling, agonist-induced GPCR activation leads to second messenger production at the plasma membrane, such as Gαs-stimulated production of cAMP by adenylyl cyclase (AC), followed by activity-dependent GPCR internalization and signaling desensitization through β-arrestin (β-arr) binding. However, several recent live-cell imaging studies using genetically encoded fluorescent biosensors have indicated that internalized GPCRs remain active and continue to signal from endosomal compartments, in some cases despite continued association with β-arr. Indirect evidence also suggests the presence of endosomal AC activity, although further studies are needed to clarify how ACs reach the endosome (indicated by a question mark), and such persistent GPCR signaling may therefore be responsible for sustained cAMP production within the cytosol, in contrast to transient cAMP production from the plasma membrane, leading to the activation of PKA signaling within the nucleus.