Endosomal generation of cAMP in GPCR signaling

Abstract

Besides signaling from the plasma membrane, evidence for noncanonical signaling by GPCRs from internal compartments has recently emerged and is highlighted in this Perspective. For the well-studied PTHR, agonists stabilize a distinct receptor conformation within endosomes, leading to sustained signaling. It has been widely assumed that the production of the ubiquitous second messenger cyclic AMP, which is mediated by cell surface G protein–coupled receptors (GPCRs), and its termination take place exclusively at the plasma membrane. Recent studies reveal that diverse GPCRs do not always follow this conventional paradigm. In the new model, GPCRs mediate G-protein signaling not only from the plasma membrane but also from endosomal membranes. This model proposes that following ligand binding and activation, cell surface GPCRs internalize and redistribute into early endosomes, where trimeric G protein signaling can be maintained for an extended period of time. This Perspective discusses the molecular and cellular mechanistic subtleties as well as the physiological consequences of this unexpected process, which is considerably changing how we think about GPCR signaling and regulation and how we study drugs that target this receptor family.