STIM1 carboxyl-terminus activates native SOC, Icrac and TRPC1 channels (original) (raw)

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+ (I crac) channels and store-operated calcium entry (SOC) channels2. Although the molecular identity and regulation of I crac and SOC channels have not been precisely determined1, notable recent findings are the identification of STIM1, which has been indicated to regulate SOC and I crac 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 I crac channels or as an I crac 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 I crac 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, I crac 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 I crac in Jurkat cells. These observations implicate STIM1 as a key regulator of activity rather than a channel component, and reveal similar regulation of SOC, I crac and TRPC channel activation by STIM1.

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

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

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

Additional access options:

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
    You can also search for this author inPubMed Google Scholar
  2. Weizhong Zeng
    You can also search for this author inPubMed Google Scholar
  3. Joo Young Kim
    You can also search for this author inPubMed Google Scholar
  4. Joseph P. Yuan
    You can also search for this author inPubMed Google Scholar
  5. Linhuang Han
    You can also search for this author inPubMed Google Scholar
  6. Shmuel Muallem
    You can also search for this author inPubMed Google Scholar
  7. Paul F. Worley
    You can also search for this author inPubMed Google Scholar

Corresponding authors

Correspondence toShmuel Muallem or Paul F. Worley.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

About this article

Cite this article

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

Download citation

This article is cited by