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Molecular basis of parathyroid hormone receptor signaling and trafficking: a family B GPCR paradigm

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Abstract

The parathyroid hormone (PTH) receptor type 1 (PTHR), a G protein-coupled receptor (GPCR), transmits signals to two hormone systems—PTH, endocrine and homeostatic, and PTH-related peptide (PTHrP), paracrine—to regulate different biological processes. PTHR responds to these hormonal stimuli by activating heterotrimeric G proteins, such as GS that stimulates cAMP production. It was thought that the PTHR, as for all other GPCRs, is only active and signals through G proteins on the cell membrane, and internalizes into a cell to be desensitized and eventually degraded or recycled. Recent studies with cultured cell and animal models reveal a new pathway that involves sustained cAMP signaling from intracellular domains. Not only do these studies challenge the paradigm that cAMP production triggered by activated GPCRs originates exclusively at the cell membrane but they also advance a comprehensive model to account for the functional differences between PTH and PTHrP acting through the same receptor.

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Acknowledgments

Original work described was supported by the National Institutes of Health grants DK087688 (J.-P.V.), DK69998 (P.A.F.), and DK11794 (T.J.G.).

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  1. Laboratory for GPCR Biology, Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, E1357 Thomas E. Starzl Biochemical Science Tower, 200 Lothrop Street, Pittsburgh, PA, 15261, USA

    Jean-Pierre Vilardaga, Guillermo Romero & Peter A. Friedman

  2. Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Jean-Pierre Vilardaga & Thomas J. Gardella

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  1. Jean-Pierre Vilardaga
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  2. Guillermo Romero
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  4. Thomas J. Gardella
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Correspondence to Jean-Pierre Vilardaga.

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Vilardaga, JP., Romero, G., Friedman, P.A. et al. Molecular basis of parathyroid hormone receptor signaling and trafficking: a family B GPCR paradigm. Cell. Mol. Life Sci. 68, 1–13 (2011). https://doi.org/10.1007/s00018-010-0465-9

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  • DOI: https://doi.org/10.1007/s00018-010-0465-9

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