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.

  • Letter
  • Published:

Tyrosine-kinase-dependent recruitment of RGS12 to the N-type calcium channel

Abstract

γ-Aminobutyric acid (GABA)B receptors couple to Go to inhibit N-type calcium channels in embryonic chick dorsal root ganglion neurons1. The voltage-independent inhibition, mediated by means of a tyrosine-kinase pathway2, is transient and lasts up to 100 seconds. Inhibition of endogenous RGS12, a member of the family of regulators of G-protein signalling, selectively alters the time course of voltage-independent inhibition. The RGS12 protein, in addition to the RGS domain, contains PDZ and PTB domains3. Fusion proteins containing the PTB domain of RGS12 alter the rate of termination of the GABAB signal, whereas the PDZ or RGS domains of RGS12 have no observable effects. Using primary dorsal root ganglion neurons in culture, here we show an endogenous agonist-induced tyrosine-kinase-dependent complex of RGS12 and the calcium channel. These results indicate that RGS12 is a multifunctional protein capable of direct interactions through its PTB domain with the tyrosine-phosphorylated calcium channel. Recruitment of RGS proteins to G-protein effectors may represent an additional mechanism for signal termination in G-protein-coupled pathways.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Effect of RGS12 on the desensitization of the N-type calcium channel.
Figure 2: Effects of two domains of RGS12 on rate of desensitization of GABAB-mediated inhibition of calcium current and the Fab fragment on the time course of termination of the GABAB-mediated response.
Figure 3: Formation of a regulated complex between RGS12 and the α1B subunit of the calcium channel.

Similar content being viewed by others

References

  1. Luebke, J. I. & Dunlap, K. Sensory neurons N-type calcium currents are inhibited by both voltage-dependent and -independent mechanisms. Pflügers Archiv. 428, 499–507 (1994).

    Article  CAS  Google Scholar 

  2. Diversé-Pierluissi, M. A., Remmers, A. E., Neubig, R. & Dunlap, K. Novel form of crosstalk between G protein and tyrosine kinase pathways. Proc. Natl Acad. Sci. USA 94, 5417–5421 (1997).

    Article  ADS  Google Scholar 

  3. De Vries, L. & Farquhar, M. G. RGS proteins: more than just GAPs for heterotrimeric G proteins. Trends Cell Biol. 9, 138–144 (1999).

    Article  CAS  Google Scholar 

  4. Diversé-Pierluissi, M., Inglese, J., Stoffel, R. H., Lefkowitz, R. J. & Dunlap, K. G protein-coupled receptor kinase mediates desensitization of norepinephrine-induced calcium current inhibition. Neuron 16, 579 –585 (1996).

    Article  Google Scholar 

  5. Diversé-Pierluissi, M. et al. RGS proteins as determinants of the rate of desensitization of neuronal calcium channels. J. Biol. Chem. 274, 14490–14494 ( 1999).

    Article  Google Scholar 

  6. De Vries, L. et al. RGS-GAIP, a GTPase-activating protein for Gαi heterotrimeric G proteins, is located on clathrin-coated vesicles. Mol. Biol. Cell. 9, 1123–1134 ( 1998).

    Article  CAS  Google Scholar 

  7. Srinivasa, S. P., Bernstein, L. S., Blumer, K. J. & Linder, M. E. Plasma membrane localization is required for RGS4 function in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA. 95, 5584–5589 (1998).

    Article  ADS  CAS  Google Scholar 

  8. Snow, B. E. et al. GTPase activating specificity of RGS12 and binding specificity of an alternatively spliced PDZ (PSD-95/Dlg/ZO-1) domain. J. Biol. Chem. 273, 17749–17755 ( 1998).

    Article  CAS  Google Scholar 

  9. Dubel, S. J. et al. Molecular cloning of the alpha-1 subunit of an omega-conotoxin-sensitive calcium channel. Proc. Natl Acad. Sci. USA 89, 5058–5062 (1992).

    Article  ADS  CAS  Google Scholar 

  10. Ahlijanian, M. K., Striessnig, J. & Catterall, W. A. Phosphorylation of an alpha 1-like subunit of an omega-conotoxin-sensitive brain calcium channel by cAMP-dependent protein kinase and protein kinase C. J. Biol. Chem. 266, 20192–20197 (1991).

    CAS  PubMed  Google Scholar 

  11. McEnery, M. W., Snowman, A. M., Sharp, A. H., Adams, M. E. & Snyder, S. H. Purified omega-conotoxin GVIA receptor of rat brain resembles a dihydropyridine-sensitive L-type calcium channel. Proc. Natl Acad. Sci. USA 88, 11095 –11099 (1991).

    Article  ADS  CAS  Google Scholar 

  12. Zeng, W. et al. The N-terminal domain of RGS4 confers receptor-selective inhibition of G protein signaling. J. Biol. Chem . 273, 34687–34690 (1998).

    Article  Google Scholar 

  13. Diversé-Pierluissi, M., Goldsmith, P. K. & Dunlap, K. Transmitter-mediated inhibition of N-type calcium current channels in sensory neurons involves multiple GTP-binding proteins and subunits. Neuron 14, 191– 200 (1994).

Download references

Acknowledgements

We thank R. Iyengar, E. Landau and R. Blitzer for reading the manuscript. This work was supported by grants from the National Institutes of Health (NINDS), New York City Speaker's Fund for Biomedical Research and Mount Sinai Dean's Incentive Fund for Innovative Research to M.D.P.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to María Diversé-Pierluissi.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schiff, M., Siderovski, D., Jordan, J. et al. Tyrosine-kinase-dependent recruitment of RGS12 to the N-type calcium channel. Nature 408, 723–727 (2000). https://doi.org/10.1038/35047093

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35047093

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

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