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  • Perspective
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Endosomal generation of cAMP in GPCR signaling

Abstract

It has been widely assumed that the production of the ubiquitous second messenger cyclic AMP, which is mediated by cell surface G protein–coupled receptors (GPCRs), and its termination take place exclusively at the plasma membrane. Recent studies reveal that diverse GPCRs do not always follow this conventional paradigm. In the new model, GPCRs mediate G-protein signaling not only from the plasma membrane but also from endosomal membranes. This model proposes that following ligand binding and activation, cell surface GPCRs internalize and redistribute into early endosomes, where trimeric G protein signaling can be maintained for an extended period of time. This Perspective discusses the molecular and cellular mechanistic subtleties as well as the physiological consequences of this unexpected process, which is considerably changing how we think about GPCR signaling and regulation and how we study drugs that target this receptor family.

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Figure 1: Classical versus endosomal signaling models of GPCR.
Figure 2: Regulation of endosomal GPCR signaling.
Figure 3: Signaling models of GPCR.
Figure 4: Endosomal PTHR signaling: from bench to bedside.
Figure 5: Differentiating PTHR conformations.

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Acknowledgements

This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under award numbers R01 DK087688 and DK102495 (to J.-P.V.) and P01 DK11794 (project I to T.J.G.).

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J.-P.V., F.G.J.-A. and T.J.G. each contributed to the writing of this manuscript.

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Correspondence to Jean-Pierre Vilardaga.

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Vilardaga, JP., Jean-Alphonse, F. & Gardella, T. Endosomal generation of cAMP in GPCR signaling. Nat Chem Biol 10, 700–706 (2014). https://doi.org/10.1038/nchembio.1611

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