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RGS2 regulates signal transduction in olfactory neurons by attenuating activation of adenylyl cyclase III

Nature volume 409, pages 1051–1055 (2001)Cite this article

Abstract

The heterotrimeric G-protein Gs couples cell-surface receptors to the activation of adenylyl cyclases and cyclic AMP production (reviewed in refs 1, 2). RGS proteins, which act as GTPase-activating proteins (GAPs) for the G-protein α-subunits αi and αq, lack such activity for αs (refs 3,4,5,6). But several RGS proteins inhibit cAMP production by Gs-linked receptors7,8. Here we report that RGS2 reduces cAMP production by odorant-stimulated olfactory epithelium membranes, in which the αs family member αolf links odorant receptors to adenylyl cyclase activation9,10. Unexpectedly, RGS2 reduces odorant-elicited cAMP production, not by acting on αolf but by inhibiting the activity of adenylyl cyclase type III, the predominant adenylyl cyclase isoform in olfactory neurons. Furthermore, whole-cell voltage clamp recordings of odorant-stimulated olfactory neurons indicate that endogenous RGS2 negatively regulates odorant-evoked intracellular signalling. These results reveal a mechanism for controlling the activities of adenylyl cyclases, which probably contributes to the ability of olfactory neurons to discriminate odours.

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Figure 1: Effects of RGS proteins on adenylyl cyclase activity.
Figure 2: RGS2 inhibits odorant- and forskolin-induced cAMP production.
Figure 3: RGS2 inhibits the activity of specific adenylyl cyclases.
Figure 4: RGS2 attenuates odorant signalling in olfactory neurons.

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References

  1. Sunahara, R. K., Dessauer, C. W. & Gilman, A. G. Complexity and diversity of mammalian adenylyl cyclases. Annu. Rev. Pharmacol. Toxicol. 36, 461–480 (1996).

    Article  CAS  Google Scholar 

  2. Hurley, J. H. Structure, mechanism, and regulation of mammalian adenylyl cyclase. J. Biol. Chem. 274, 7599–7602 (1999).

    Article  CAS  Google Scholar 

  3. Hepler, J. R. Emerging roles for RGS proteins in cell signaling. Trends Pharmacol. Sci. 20, 376–382 (1999).

    Article  CAS  Google Scholar 

  4. Kehrl, J. H. Heterotrimeric G protein signaling: roles in immune function and fine-tuning by RGS proteins. Immunity 8, 1–10 (1998).

    Article  CAS  Google Scholar 

  5. Sunahara, R. K., Tesmer, J. J., Gilman, A. G. & Sprang, S. R. Crystal structure of the adenylyl cyclase activator Gsα. Science 278, 1943–1947 (1997).

    Article  ADS  CAS  Google Scholar 

  6. Natochin, M. & Artemyev, N. O. A single mutation Asp229→Ser confers upon Gsα the ability to interact with regulators of G protein signaling. Biochemistry 37, 13776–13780 (1998).

    Article  CAS  Google Scholar 

  7. Chatterjee, T. K., Eapen, A. K. & Fisher, R. A. A truncated form of RGS3 negatively regulates G protein-coupled receptor stimulation of adenylyl cyclase and phosphoinositide phospholipase C. J. Biol. Chem. 272, 15481–15487 (1997).

    Article  CAS  Google Scholar 

  8. Tseng, C. C. & Zhang, X. Y. Role of regulator of G protein signaling in desensitization of the glucose-dependent insulinotropic peptide receptor. Endocrinology 139, 4470–4475 (1998).

    Article  CAS  Google Scholar 

  9. Schild, D. & Restrepo, D. Transduction mechanisms in vertebrate olfactory receptor cells. Physiol. Rev. 78, 429–466 (1998).

    Article  CAS  Google Scholar 

  10. Reed, R. R. Signaling pathways in odorant detection. Neuron 8, 205–209 (1992).

    Article  CAS  Google Scholar 

  11. Pace, U., Hanski, E., Salomon, Y. & Lancet, D. Odorant sensitive adenylate cyclase may mediate olfactory reception. Nature 316, 255–258 (1985).

    Article  ADS  CAS  Google Scholar 

  12. Sklar, P. B., Anholt, R. R. & Synder, S. H. The odorant-sensitive adenylate cyclase of olfactory receptor cells. Differential stimulation by distinct classes of odorants. J. Biol. Chem. 261, 15538–15543 (1986).

    CAS  PubMed  Google Scholar 

  13. Dessauer, C. W., Tesmer, J. J., Sprang, S. R. & Gilman, A. G. Identification of a Giα binding site on type V adenylyl cyclase. J. Biol. Chem. 273, 25831–25839 (1998).

    Article  CAS  Google Scholar 

  14. Landis, C. A. et al. GTPase inhibiting mutations activate the alpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature 340, 692–696 (1989).

    Article  ADS  CAS  Google Scholar 

  15. Bakalyar, H. A. & Reed, R. R. Identification of a specialized adenylyl cyclase that may mediate odorant detection. Science 250, 1403–1406 (1990).

    Article  ADS  CAS  Google Scholar 

  16. Firestein, S. & Weblin, F. Odor-induced membrane currents in vertebrate olfactory receptor neurons. Science 244, 79–82 (1989).

    Article  ADS  CAS  Google Scholar 

  17. Kleene, S. J. & Gesteland, R. C. Calcium-activated chloride conductance in frog olfactory cilia. J. Neurosci. 6, 3624–3629 (1991).

    Article  Google Scholar 

  18. Kurahashi, T. & Taw, K.-W. Co-existence of cationic and chloride components in odorant-induced current of vertebrate olfactory receptor cells. Nature 363, 71–74 (1993).

    Article  ADS  CAS  Google Scholar 

  19. Pepperl, D. J., Shah-Basu, S., VanLeeuwen, D., Granneman, J. G. & MacKenzie, R. G. Regulation of RGS mRNAs by cAMP in PC12 cells. Biochem. Biophys. Res. Commun. 243, 52–55 (1998).

    Article  CAS  Google Scholar 

  20. Beadling, C., Druey, K. M., Richter, G., Kehrl, J. H. & Smith, K. A. Regulators of G protein signaling exhibit distinct patterns of gene expression and target G protein specificity in human lymphocytes. J. Immunol. 162, 2677–2682 (1999).

    CAS  PubMed  Google Scholar 

  21. Wei, J. et al. Phosphorylation and inhibition of olfactory adenylyl cyclase by CaM kinase II in Neurons: a mechanism for attenuation of olfactory signals. Neuron 21, 495–504 (1998).

    Article  CAS  Google Scholar 

  22. Sinnarajah, S. et al. Inhibition and enhancement of odorant-induced cAMP accumulation in rat olfactory cilia by antibodies directed against Gαs/olf- and Gαi-protein subunits. FEBS Lett. 426, 377–380 (1998).

    Article  CAS  Google Scholar 

  23. Summers, M. D. & Smith, G. E. in Texas Agricultural Experiment Station Bulletin 1,555 (College Station, Texas, 1987).

    Google Scholar 

  24. Salomon, Y., Londos, C. & Rodbell, M. A highly sensitive adenylate cyclase assay. Anal. Biochem. 58, 541–548 (1974).

    Article  CAS  Google Scholar 

  25. Firestein, S. & Werblin, F. in Chemical Senses Vol. 1, Receptor Events and Transduction in Taste and Olfaction (eds Brand, J. G. et al.) 449–467 (Marcel Dekker, New York, 1989).

    Google Scholar 

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Acknowledgements

We thank M. Rust for editorial assistance; K. Druey, H. Cho and A. Sheschonka for the recombinant RGS proteins; and A. Fauci for support. E.M. and V.V. were supported by grants from the Office of Special Technology, Federal Aviation Administration and Defense Advanced Research Project Agency. C.W.D. was supported by the American Heart Association and the National Institutes of Health.

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Authors and Affiliations

  1. B cell Molecular Biology Section, Laboratory of Immunoregulation, NIAID, NIH, Bethesda, 20892, Maryland, USA

    Srikumar Sinnarajah, Deepa Srikumar, John Yuen & John H. Kehrl

  2. Department of Integrative Biology and Pharmacology, University of Texas-Houston Medical School, Houston, 77225, Texas, USA

    Carmen W. Dessauer & Jun Chen

  3. Department of Anatomy, Physiology, and Pharmacology, Auburn University, Auburn, 36849, Alabama, USA

    Solomon Yilma, John C. Dennis, Edward E. Morrison & Vitaly Vodyanoy

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  1. Srikumar Sinnarajah
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Correspondence to John H. Kehrl.

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Sinnarajah, S., Dessauer, C., Srikumar, D. et al. RGS2 regulates signal transduction in olfactory neurons by attenuating activation of adenylyl cyclase III. Nature 409, 1051–1055 (2001). https://doi.org/10.1038/35059104

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