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β2-adrenergic receptor control of endosomal PTH receptor signaling via Gβγ

Nature Chemical Biology volume 13, pages 259–261 (2017)Cite this article

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Abstract

Cells express several G-protein-coupled receptors (GPCRs) at their surfaces, transmitting simultaneous extracellular hormonal and chemical signals into cells. A comprehensive understanding of mechanisms underlying the integrated signaling response induced by distinct GPCRs is thus required. Here we found that the β2-adrenergic receptor, which induces a short cAMP response, prolongs nuclear cAMP and protein kinase A (PKA) activation by promoting endosomal cAMP production in parathyroid hormone (PTH) receptor signaling through the stimulatory action of G protein Gβγ subunits on adenylate cyclase type 2.

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Figure 1: Synergistic action of β2AR on PTHR signaling.
Figure 2: Gβγ and AC2 control of endosomal cAMP production by PTH.

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Acknowledgements

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the US National Institutes of Health (NIH) under Award numbers R01 DK087688 and R01 DK102495 (J.-P.V.), and K01AR062598 (J.M.T.), and the Cotswold Foundation Fellowship Award (F.G.J.-A.). The authors thank P. Friedman (University of Pittsburgh) for critical discussion, T. Gardella (Mass general hospital) for providing PTHTMR, and M. Bastepe (Mass general hospital) for providing GαS-knockout MEF cells.

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Authors and Affiliations

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

    Frédéric G Jean-Alphonse, Vanessa L Wehbi, Kunhong Xiao & Jean-Pierre Vilardaga

  2. Department of Biomedical Engineering, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Jingming Chen & Juan M Taboas

  3. Department of Molecular Pharmacology, Medical Research Institute Tokyo Medical and Dental University, Bunkyo-Ku, Tokyo, Japan.,

    Masaki Noda

  4. McGowan Institute of Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

    Juan M Taboas

Authors
  1. Frédéric G Jean-Alphonse
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  4. Masaki Noda
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  7. Jean-Pierre Vilardaga
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Contributions

F.G.J.-A. performed all the experiments with the support of V.L.W. and J.C. K.X., provided expertise and supervised proteomic experiments. M.N. provided expertise with ROS17/2.8 cells. J.M.T. provided expertise with culture of primary osteoblasts, and J.-P.V. was responsible for the overall concept of the study, as well as writing of the manuscript and data analysis with F.G.J.-A.

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Correspondence to Jean-Pierre Vilardaga.

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The authors declare no competing financial interests.

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Supplementary Results, Supplementary Tables 1 and 2 and Supplementary Figures 1–16. (PDF 863 kb)

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Jean-Alphonse, F., Wehbi, V., Chen, J. et al. β2-adrenergic receptor control of endosomal PTH receptor signaling via Gβγ. Nat Chem Biol 13, 259–261 (2017). https://doi.org/10.1038/nchembio.2267

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