Noncanonical GPCR signaling arising from a PTH receptor-arrestin-Gβγ complex

Proc Natl Acad Sci U S A. 2013 Jan 22;110(4):1530-5. doi: 10.1073/pnas.1205756110. Epub 2013 Jan 7.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Arrestins / chemistry
  • Arrestins / metabolism*
  • Cyclic AMP / biosynthesis
  • Fluorescence Resonance Energy Transfer
  • GTP-Binding Protein beta Subunits / chemistry
  • GTP-Binding Protein beta Subunits / metabolism*
  • GTP-Binding Protein gamma Subunits / chemistry
  • GTP-Binding Protein gamma Subunits / metabolism*
  • HEK293 Cells
  • Humans
  • Kinetics
  • Models, Biological
  • Multiprotein Complexes / chemistry
  • Multiprotein Complexes / metabolism
  • Parathyroid Hormone / metabolism
  • Parathyroid Hormone / pharmacology
  • Receptor, Parathyroid Hormone, Type 1 / chemistry
  • Receptor, Parathyroid Hormone, Type 1 / metabolism*
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / metabolism*
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction
  • beta-Arrestins

Substances

  • Arrestins
  • G-protein Beta gamma
  • GTP-Binding Protein beta Subunits
  • GTP-Binding Protein gamma Subunits
  • Multiprotein Complexes
  • Parathyroid Hormone
  • Receptor, Parathyroid Hormone, Type 1
  • Receptors, G-Protein-Coupled
  • Recombinant Fusion Proteins
  • beta-Arrestins
  • Cyclic AMP