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A naturally occurring isoform inhibits parathyroid hormone receptor trafficking and signaling†‡

  1. Verónica Alonso1,*,
  2. Juan A Ardura1,*,
  3. Bin Wang1,
  4. W Bruce Sneddon1,2,
  5. Peter A Friedman1,*

Article first published online: 24 JUN 2010

DOI: 10.1002/jbmr.167

Issue

Journal of Bone and Mineral Research

Journal of Bone and Mineral Research

Volume 26, Issue 1, pages 143–155, January 2011

Additional Information

How to Cite

Alonso, V., Ardura, J. A., Wang, B., Sneddon, W. B. and Friedman, P. A. (2011), A naturally occurring isoform inhibits parathyroid hormone receptor trafficking and signaling. J Bone Miner Res, 26: 143–155. doi: 10.1002/jbmr.167

Author Information

  1. 1

    Laboratory for G Protein–Coupled Receptor Biology, Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

  2. 2

    Department of Biological Sciences, Duquesne University, Pittsburgh, PA, USA

*University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, W1340 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261, USA.

  1. †

    V Alonso and JA Ardura contributed equally to this work.

  2. ‡

    Additional Supporting Information may be found in the online version of this article.

Publication History

  1. Issue published online: 22 DEC 2010
  2. Article first published online: 24 JUN 2010
  3. Accepted manuscript online: 24 JUN 2010 12:00AM EST
  4. Manuscript Accepted: 11 JUN 2010
  5. Manuscript Revised: 20 MAY 2010
  6. Manuscript Received: 17 MAR 2010

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Keywords:

  • PTH RECEPTOR;
  • ISOFORM;
  • DOMINANT-NEGATIVE;
  • ALTERNATIVE SPLICING;
  • G PROTEIN–COUPLED RECEPTORS;
  • MEMBRANE TRAFFICKING;
  • MAP KINASE;
  • ADENYLYL CYCLASE

Abstract

Parathyroid hormone (PTH) regulates calcium homeostasis and bone remodeling through its cognitive receptor (PTHR). We describe here a PTHR isoform harboring an in-frame 42-bp deletion of exon 14 (Δe14-PTHR) that encodes transmembrane domain 7. Δe14-PTHR was detected in human kidney and buccal epithelial cells. We characterized its topology, cellular localization, and signaling, as well as its interactions with PTHR. The C-terminus of the Δe14-PTHR is extracellular, and cell surface expression is strikingly reduced compared with the PTHR. Δe14-PTHR displayed impaired trafficking and accumulated in endoplasmic reticulum. Signaling and activation of cAMP and ERK by Δe14-PTHR was decreased significantly compared with PTHR. Δe14-PTHR acts as a functional dominant-negative by suppressing the action of PTHR. Cells cotransfected with both receptors exhibit markedly reduced PTHR cell membrane expression, colocalization with Δe14-PTHR in endoplasmic reticulum, and diminished cAMP activation and ERK phosphorylation in response to challenge with PTH. Δe14-PTHR forms heterodimers with PTHR, which may account for cytoplasmic retention of PTHR in the presence of Δe14-PTHR. Analysis of the PTHR heteronuclear RNA suggests that base-pair complementarity in introns surrounding exon 14 causes exon skipping and accounts for generation of the Δe14-PTHR isoform. Thus Δe14-PTHR is a poorly functional receptor that acts as a dominant-negative of PTHR trafficking and signaling and may contribute to PTH resistance. © 2011 American Society for Bone and Mineral Research.

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