title: Noncanonical GPCR signaling arising from a PTH receptor-arrestin-Gβγ complex.
abstract: G protein-coupled receptors (GPCRs) participate in ubiquitous transmembrane signal transduction processes by activating heterotrimeric G proteins. In the current "canonical" model of GPCR signaling, arrestins terminate receptor signaling by impairing receptor-G-protein coupling and promoting receptor internalization. However, parathyroid hormone receptor type 1 (PTHR), an essential GPCR involved in bone and mineral metabolism, does not follow this conventional desensitization paradigm. β-Arrestins prolong G protein (G(S))-mediated cAMP generation triggered by PTH, a process that correlates with the persistence of arrestin-PTHR complexes on endosomes and which is thought to be associated with prolonged physiological calcemic and phosphate responses. This presents an inescapable paradox for the current model of arrestin-mediated receptor-G-protein decoupling. Here we show that PTHR forms a ternary complex that includes arrestin and the Gβγ dimer in response to PTH stimulation, which in turn causes an accelerated rate of G(S) activation and increases the steady-state levels of activated G(S), leading to prolonged generation of cAMP. This work provides the mechanistic basis for an alternative model of GPCR signaling in which arrestins contribute to sustaining the effect of an agonist hormone on the receptor.
authors.affiliation: Laboratory for G Protein-Coupled Receptor Biology, Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA.
authors.forename: Vanessa L
authors.initials: VL
authors.lastname: Wehbi
authors.forename: Hilary P
authors.initials: HP
authors.lastname: Stevenson
authors.forename: Timothy N
authors.initials: TN
authors.lastname: Feinstein
authors.forename: Guillermo
authors.initials: G
authors.lastname: Calero
authors.forename: Guillermo
authors.initials: G
authors.lastname: Romero
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Vilardaga
mesh_terms: D019390:Arrestins / Q000737:chemistry / Q000378:metabolism*; D000242:Cyclic AMP / Q000096:biosynthesis; D031541:Fluorescence Resonance Energy Transfer; D044387:GTP-Binding Protein beta Subunits / Q000737:chemistry / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D010281:Parathyroid Hormone / Q000378:metabolism / Q000494:pharmacology; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000737:chemistry / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; C118981:G-protein Beta gamma; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D046912:Multiprotein Complexes; D010281:Parathyroid Hormone; D044168:Receptor, Parathyroid Hormone, Type 1; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; D000071557:beta-Arrestins; D000242:Cyclic AMP