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  • Review Article
  • Published:

PTH receptor-1 signalling—mechanistic insights and therapeutic prospects

Nature Reviews Endocrinology volume 11, pages 712–724 (2015)Cite this article

Subjects

Key Points

  • Parathyroid hormone (PTH)/parathyroid hormone-related protein (PTHrP) receptor (PTHR1) mediates the biological actions of two endogenous ligands, PTH and PTHrP and has key roles in regulating blood calcium levels and tissue development

  • PTH and PTHrP interact with PTHR1 through similar, although not identical mechanisms, and preferentially stabilize distinct receptor conformations

  • Certain structurally distinct PTH and PTHrP ligand analogues, which stabilize distinct receptor conformations, induce altered signalling responses that differ in signal type and duration

  • Prolonged signalling by certain PTH ligand analogues correlates temporally with ligand–receptor complexes located in endosomes, which suggests mechanisms of signal generation and termination distinct from those described by traditional G-protein-coupled receptor models

  • Consideration of ligand-based mechanisms that control signal duration provide insight into the processes of receptor dysfunction, as wells as guidance for addressing PTHR1-related diseases

  • Identification and incorporation of specific structural features that promote or prevent long-lasting biological responses hold promise for the design of treatments for hypoparathyroidism and osteoporosis, respectively

Abstract

Parathyroid hormone/parathyroid hormone-related protein receptor (PTH/PTHrP type 1 receptor; commonly known as PTHR1) is a family B G-protein-coupled receptor (GPCR) that regulates skeletal development, bone turnover and mineral ion homeostasis. PTHR1 transduces stimuli from PTH and PTHrP into the interior of target cells to promote diverse biochemical responses. Evaluation of the signalling properties of structurally modified PTHR1 ligands has helped to elucidate determinants of receptor function and mechanisms of downstream cellular and physiological responses. Analysis of PTHR1 responses induced by structurally modified ligands suggests that PTHR1 can continue to signal through a G-protein-mediated pathway within endosomes. Such findings challenge the longstanding paradigm in GPCR biology that the receptor is transiently activated at the cell membrane, followed by rapid deactivation and receptor internalization. Evaluation of structurally modified PTHR1 ligands has further led to the identification of ligand analogues that differ from PTH or PTHrP in the type, strength and duration of responses induced at the receptor, cellular and organism levels. These modified ligands, and the biochemical principles revealed through their use, might facilitate an improved understanding of PTHR1 function in vivo and enable the treatment of disorders resulting from defects in PTHR1 signalling. This Review discusses current understanding of PTHR1 modes of action and how these findings might be applied in future therapeutic agents.

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Figure 1: Altered modes of cAMP signalling at PTHR1.
Figure 2: Distinct mechanisms of prolonged PTH analogue action in vivo.

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Acknowledgements

R.W.C. was supported in part by a Biotechnology Training Grant from NIGMS (T32 GM008349). Work in the authors laboratories was supported by NIH grants R01-GM056414 (S.H.G.), RO1-DK087688, R01-DK102495 (J.-P.V.) and P01-DK11794 (T.J.G.).

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Authors and Affiliations

  1. Department of Chemistry, 1101 University Avenue, University of Wisconsin, Madison, 53706, WI, USA

    Ross W. Cheloha & Samuel H. Gellman

  2. Department of Pharmacology and Chemical Biology, Laboratory for GPCR Biology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, 15213, PA, USA

    Jean-Pierre Vilardaga

  3. Endocrine Unit, Massachusetts General Hospital, 50 Blossom Street, Boston, 02114, MA, USA

    Thomas J. Gardella

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  1. Ross W. Cheloha
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  2. Samuel H. Gellman
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  4. Thomas J. Gardella
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All authors researched data for the article, provided substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Thomas J. Gardella.

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Cheloha, R., Gellman, S., Vilardaga, JP. et al. PTH receptor-1 signalling—mechanistic insights and therapeutic prospects. Nat Rev Endocrinol 11, 712–724 (2015). https://doi.org/10.1038/nrendo.2015.139

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