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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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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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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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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DOI: https://doi.org/10.1038/nchembio.2267
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