[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
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:

STIM1 carboxyl-terminus activates native SOC, Icrac and TRPC1 channels

Nature Cell Biology volume 8, pages 1003–1010 (2006)Cite this article

Abstract

Receptor-evoked Ca2+ signalling involves Ca2+ release from the endoplasmic reticulum, followed by Ca2+ influx across the plasma membrane1. Ca2+ influx is essential for many cellular functions, from secretion to transcription, and is mediated by Ca2+-release activated Ca2+ (Icrac) channels and store-operated calcium entry (SOC) channels2. Although the molecular identity and regulation of Icrac and SOC channels have not been precisely determined1, notable recent findings are the identification of STIM1, which has been indicated to regulate SOC and Icrac channels by functioning as an endoplasmic reticulum Ca2+ sensor3,4,5,6, and ORAI1 (ref. 7) or CRACM1 (ref. 8) — both of which may function as Icrac channels or as an Icrac subunit. How STIM1 activates the Ca2+ influx channels and whether STIM1 contributes to the channel pore remains unknown. Here, we identify the structural features that are essential for STIM1-dependent activation of SOC and Icrac channels, and demonstrate that they are identical to those involved in the binding and activation of TRPC1. Notably, the cytosolic carboxyl terminus of STIM1 is sufficient to activate SOC, Icrac and TRPC1 channels even when native STIM1 is depleted by small interfering RNA. Activity of STIM1 requires an ERM domain, which mediates the selective binding of STIM1 to TRPC1, 2 and 4, but not to TRPC3, 6 or 7, and a cationic lysine-rich region, which is essential for gating of TRPC1. Deletion of either region in the constitutively active STIM1D76A yields dominant-negative mutants that block native SOC channels, expressed TRPC1 in HEK293 cells and Icrac in Jurkat cells. These observations implicate STIM1 as a key regulator of activity rather than a channel component, and reveal similar regulation of SOC, Icrac and TRPC channel activation by STIM1.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: The EF-hand mutant and cytosolic fragment of STIM1 activate endogenous SOC channels in HEK293 cells.
Figure 2: STIM1 and TRPC1 interaction and punctae formation.
Figure 3: The ERM domain of STIM1 binds TRPC channels, and the cationic lysines in the lysine-rich tail are essential for SOC-channel activation.
Figure 4: Effect of STIM1 constructs on TRPC1 activity.
Figure 5: The STIM1D76Afull-length and the carboxyl terminus activate Icrac channels in Jurkat T cells, and require the ERM domain and the lysine-rich tail.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Parekh, A. B. & Putney, J. W., Jr. Store-operated calcium channels. Physiol. Rev. 85, 757–810 (2005).

    Article  CAS  Google Scholar 

  2. Berridge, M. J., Bootman, M. D. & Roderick, H. L. Calcium signalling: dynamics, homeostasis and remodelling. Nature Rev. Mol. Cell Biol. 4, 517–529 (2003).

    Article  CAS  Google Scholar 

  3. Spassova, M. A. et al. STIM1 has a plasma membrane role in the activation of store-operated Ca2+ channels. Proc. Natl Acad. Sci. USA 103, 4040–4045 (2006).

    Article  CAS  Google Scholar 

  4. Zhang, S. L. et al. STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature 437, 902–905 (2005).

    Article  CAS  Google Scholar 

  5. Roos, J. et al. STIM1, an essential and conserved component of store-operated Ca2+ channel function. J. Cell Biol. 169, 435–445 (2005).

    Article  CAS  Google Scholar 

  6. Liou, J. et al. STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr. Biol. 15, 1235–1241 (2005).

    Article  CAS  Google Scholar 

  7. Feske, S. et al. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441, 179–186 (2006).

    Article  CAS  Google Scholar 

  8. Vig, M. et al. CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 312, 1220–1223 (2006).

    Article  CAS  Google Scholar 

  9. Williams, R. T. et al. Identification and characterization of the STIM (stromal interaction molecule) gene family: coding for a novel class of transmembrane proteins. Biochem. J. 357, 673–685 (2001).

    Article  CAS  Google Scholar 

  10. Crabtree, G. R. & Olson, E. N. NFAT signaling: choreographing the social lives of cells. Cell 109 (Suppl.), S67–S79 (2002).

    Article  CAS  Google Scholar 

  11. Freichel, M. et al. Functional role of TRPC proteins in native systems: implications from knockout and knock-down studies. J. Physiol. 567, 59–66 (2005).

    Article  CAS  Google Scholar 

  12. Lintschinger, B. et al. Coassembly of Trp1 and Trp3 proteins generates diacylglycerol- and Ca2+-sensitive cation channels. J. Biol. Chem. 275, 27799–27805 (2000).

    CAS  PubMed  Google Scholar 

  13. Northrop, J. P., Ullman, K. S. & Crabtree, G. R. Characterization of the nuclear and cytoplasmic components of the lymphoid-specific nuclear factor of activated T cells (NFAT) complex. J. Biol. Chem. 268, 2917–2923 (1993).

    CAS  PubMed  Google Scholar 

  14. Northrop, J. P. et al. NFAT components define a family of transcription factors targeted in T-cell activation. Nature 369, 497–502 (1994).

    Article  CAS  Google Scholar 

  15. Tsai, R. Y. & Reed, R. R. Using a eukaryotic GST fusion vector for proteins difficult to express in E. coli. Biotechniques 23, 794–796, 798, 800 (1997).

    Article  CAS  Google Scholar 

  16. Sun, L. et al. Cabin 1, a negative regulator for calcineurin signaling in T lymphocytes. Immunity 8, 703–711 (1998).

    Article  CAS  Google Scholar 

  17. Yuan, J. P. et al. Homer binds TRPC family channels and is required for gating of TRPC1 by IP3 receptors. Cell 114, 777–789 (2003).

    Article  CAS  Google Scholar 

  18. Xiao, B. et al. Homer regulates the association of group 1 metabotropic glutamate receptors with multivalent complexes of homer-related, synaptic proteins. Neuron 21, 707–716 (1998).

    Article  CAS  Google Scholar 

  19. Kozak, J. A., Kerschbaum, H. H. & Cahalan, M. D. Distinct properties of CRAC and MIC channels in RBL cells. J. Gen. Physiol. 120, 221–235 (2002).

    Article  Google Scholar 

Download references

Acknowledgements

We thank J. Liu (Johns Hopkins University) for the plasmids NFAT1–GFP (HA–mNFAT1(1–460)–GFP), pNFAT-luc, pAP1-luc and pSV40-β-galactosidase; and T. Meyer (Stanford University) for the plasmid YFP–STIM1. Research was supported by grants from the National Institute on Drug Abuse (NIDA; DA00266, DA10309) and the National Institute of Mental Health (NIMH; MH068830) to P.F.W., and the National Institute of Dental and Craniofacial Research (NIDCR) and National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) to S.M.

Author information

Author notes

  1. Guo N. Huang and Weizhong Zeng: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA

    Guo N. Huang, Linhuang Han & Paul F. Worley

  2. Program in Biochemistry, Cellular and Molecular Biology, The Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA

    Guo N. Huang

  3. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, 75390, TX, USA

    Weizhong Zeng, Joo Young Kim, Joseph P. Yuan & Shmuel Muallem

  4. Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA

    Paul F. Worley

Authors
  1. Guo N. Huang
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Weizhong Zeng
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Joo Young Kim
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Joseph P. Yuan
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Linhuang Han
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Shmuel Muallem
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Paul F. Worley
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding authors

Correspondence to Shmuel Muallem or Paul F. Worley.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Figures S1, S2, S3 and S4 (PDF 672 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, G., Zeng, W., Kim, J. et al. STIM1 carboxyl-terminus activates native SOC, Icrac and TRPC1 channels. Nat Cell Biol 8, 1003–1010 (2006). https://doi.org/10.1038/ncb1454

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1454

Search

Advanced 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