Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • NEWS AND VIEWS

Activation mechanisms for a universal signalling protein

Computational and biochemical studies have revealed the mechanisms by which arrestin proteins are activated by G-protein-coupled receptors — potentially opening up broad avenues for drug discovery.
  1. Brian Krumm

    1. Brian Krumm is in the Department of Pharmacology, School of Medicine, and the Division of Medicinal Chemistry and Chemical Biology, Eshelman School of Pharmacy, and in the NIMH Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill, North Carolina 27705, USA.

    View author publications

    You can also search for this author in PubMed  Google Scholar

  2. Bryan L. Roth

    1. Bryan L. Roth is in the Department of Pharmacology, School of Medicine, and the Division of Medicinal Chemistry and Chemical Biology, Eshelman School of Pharmacy, and in the NIMH Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill, North Carolina 27705, USA.

    View author publications

    You can also search for this author in PubMed  Google Scholar

The largest family of drug targets in humans, and the principal therapeutic targets for at least 30% of approved medications in the United States, are the G-protein-coupled receptors1 (GPCRs). When these transmembrane proteins detect extracellular agonist molecules, they transmit signals to the cell interior through G proteins inside the cells. The receptor is then sequentially phosphorylated to attenuate further signalling. The phosphorylated GPCR binds to an arrestin protein, and both undergo conformational changes that lead to the activation of arrestin-dependent cellular processes. Two papers in Nature, by Eichel et al.2 and Latorraca et al.3, now provide fresh insights into the mechanisms of arrestin activation and its consequences. Given the enormous potential of drugs that selectively target either G-protein or arrestin signalling, these findings might accelerate the development of safer and more-effective medications for a wide range of conditions.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Nature 557, 318-319 (2018)

doi: https://doi.org/10.1038/d41586-018-04977-6

References

  1. Sriram, K. & Insel, P. A. Mol. Pharmacol. 93, 251–258 (2018).

    Article  PubMed  Google Scholar 

  2. Eichel, K. et al. Nature 557, 381–386 (2018).

    Article  Google Scholar 

  3. Latorraca, N. R. et al. Nature 557, 452–456 (2018).

    Article  Google Scholar 

  4. Wilden, U., Hall, S. W. & Kühn, H. Proc. Natl Acad. Sci. USA 83, 1174–1178 (1986).

    Article  PubMed  CAS  Google Scholar 

  5. Luttrell, L. M. & Lefkowitz, R. J. J. Cell Sci. 115, 455–465 (2002).

    PubMed  CAS  Google Scholar 

  6. Palczewski, K., Buczyłko, J., Imami, N. R., McDowell, J. H. & Hargrave, P. A. J. Biol. Chem. 266, 15334–15339 (1991).

    PubMed  CAS  Google Scholar 

  7. Wu, G., Krupnick, J. G., Benovic, J. L. & Lanier, S. M. J. Biol. Chem. 272, 17836–17842 (1997).

    Article  PubMed  CAS  Google Scholar 

  8. Gelber, E. I. et al. J. Neurochem. 72, 2206–2214 (1999).

    Article  PubMed  CAS  Google Scholar 

  9. Kang, Y. et al. Nature 523, 561–567 (2015).

    Article  PubMed  CAS  Google Scholar 

  10. Zhou, X. E. et al. Cell 170, 457–469 (2017).

    Article  PubMed  CAS  Google Scholar 

  11. Eichel, K., Jullié, D. & von Zastrow, M. Nature Cell Biol. 18, 303–310 (2016).

    Article  PubMed  CAS  Google Scholar 

  12. Bhatnagar, A. et al. J. Biol. Chem. 276, 8269–8277 (2001).

    Article  PubMed  CAS  Google Scholar 

  13. Luttrell, L. M. et al. Science 283, 655–661 (1999).

    Article  PubMed  CAS  Google Scholar 

  14. Wacker, D., Stevens, R. C. & Roth, B. L. Cell 170, 414–427 (2017).

    Article  PubMed  CAS  Google Scholar 

  15. Smith, J. S., Lefkowitz, R. J. & Rajagopal, S. Nature Rev. Drug Discov. 17, 243–260 (2018).

    Article  PubMed  CAS  Google Scholar 

Download references

Subjects

Latest on:

Nature Careers

Jobs

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing

Search

Advanced search

Quick links