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Endosomal PTH Receptor Signaling Through cAMP and Its Consequence for Human Medicine

  • Ieva Sutkeviciute
  • Frederic G. Jean-Alphonse
  • Jean-Pierre Vilardaga
Chapter
Part of the Topics in Medicinal Chemistry book series

Abstract

The parathyroid hormone (PTH) type 1 receptor (PTHR) is a medically important G protein-coupled receptor (GPCR) that triggers the cAMP/PKA signaling pathway in kidney and bone cells to regulate calcium ion homeostasis and bone turnover. It has been generally assumed that the production of cAMP mediated by GPCR and its termination take place exclusively at the plasma membrane. Recent studies reveal that the PTHR does not always follow this conventional paradigm. In the new model, PTH induces a prolonged cAMP response that is derived from the internalized ligand–PTHR complex located within endosomes. This model has been recognized as a new paradigm of GPCR signaling for peptide hormones, and the PTHR is a prototypical example. In this chapter we discuss molecular, structural, and cellular mechanisms responsible for this unexpected signaling process and its biological consequences.

Keywords

Arrestin Endosomal signaling GPCR Hypocalcemia PTH receptor Retromer 

Notes

Acknowledgments

This work was supported by the National Institutes of Health (NIH) under Award numbers R01 DK087688 and R01 DK102495 (JPV), and the Cotswold Foundation Fellowship Award (FJA).

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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Ieva Sutkeviciute
    • 1
  • Frederic G. Jean-Alphonse
    • 1
  • Jean-Pierre Vilardaga
    • 1
  1. 1.Laboratory for GPCR Biology, Department of Pharmacology and Chemical BiologyUniversity of Pittsburgh School of MedicinePittsburghUSA

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