title: Endosomal generation of cAMP in GPCR signaling.
abstract: 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.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Vilardaga
authors.forename: Frederic G
authors.initials: FG
authors.lastname: Jean-Alphonse
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Gardella
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis*; D011992:Endosomes / Q000378:metabolism*; D006801:Humans; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP