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

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Structure and Function of GPCRs

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 30))

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.

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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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Authors and Affiliations

  1. Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15217, USA

    Ieva Sutkeviciute, Frederic G. Jean-Alphonse & Jean-Pierre Vilardaga

Authors
  1. Ieva Sutkeviciute
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  2. Frederic G. Jean-Alphonse
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  3. Jean-Pierre Vilardaga
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Correspondence to Jean-Pierre Vilardaga .

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Editors and Affiliations

  1. Institut de Génomique Fonctionnelle Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM), University of Montpellier, Montpellier, France

    Guillaume Lebon

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Sutkeviciute, I., Jean-Alphonse, F.G., Vilardaga, JP. (2017). Endosomal PTH Receptor Signaling Through cAMP and Its Consequence for Human Medicine. In: Lebon, G. (eds) Structure and Function of GPCRs. Topics in Medicinal Chemistry, vol 30. Springer, Cham. https://doi.org/10.1007/7355_2017_1

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