title: Retromer terminates the generation of cAMP by internalized PTH receptors.
abstract: The generation of cAMP by G protein-coupled receptors (GPCRs) and its termination are currently thought to occur exclusively at the plasma membrane of cells. Under existing models of receptor regulation, this signal is primarily restricted by desensitization of the receptors through their binding to β-arrestins. However, this paradigm is not consistent with recent observations that the parathyroid hormone receptor type 1 (PTHR) continues to stimulate cAMP production even after receptor internalization, as β-arrestins are known to rapidly bind and internalize activated PTHR. Here we show that binding to β-arrestin1 prolongs rather than terminates the generation of cAMP by PTHR, and that cAMP generation correlates with the persistence of arrestin-receptor complexes on endosomes. PTHR signaling is instead turned off by the retromer complex, which regulates the movement of internalized receptor from endosomes to the Golgi apparatus. Thus, binding by the retromer complex regulates the sustained generation of cAMP triggered by an internalized GPCR.
authors: Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA.
authors: Timothy N
authors: TN
authors: Feinstein
authors: Vanessa L
authors: VL
authors: Wehbi
authors: Juan A
authors: JA
authors: Ardura
authors: David S
authors: DS
authors: Wheeler
authors: Sebastien
authors: S
authors: Ferrandon
authors: Thomas J
authors: TJ
authors: Gardella
authors: Jean-Pierre
authors: JP
authors: Vilardaga
mesh_terms: D019390:Arrestins / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D011992:Endosomes / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D006056:Golgi Apparatus / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008954:Models, Biological; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D044168:Receptor, Parathyroid Hormone, Type 1; D000071557:beta-Arrestins; D000242:Cyclic AMP