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.

  • Article
  • Published:

Temperature-dependent STIM1 activation induces Ca2+ influx and modulates gene expression

Abstract

Intracellular Ca2+ is essential for diverse cellular functions. Ca2+ entry into many cell types including immune cells is triggered by depleting endoplasmic reticulum (ER) Ca2+, a process termed store-operated Ca2+ entry (SOCE). STIM1 is an ER Ca2+ sensor. Upon Ca2+ store depletion, STIM1 clusters at ER–plasma membrane junctions where it interacts with and gates Ca2+-permeable Orai1 ion channels. Here we show that STIM1 is also activated by temperature. Heating cells caused clustering of STIM1 at temperatures above 35 °C without depleting Ca2+ stores and led to Orai1-mediated Ca2+ influx as a heat off-response (response after cooling). Notably, the functional coupling of STIM1 and Orai1 is prevented at high temperatures, potentially explaining the heat off-response. Additionally, physiologically relevant temperature shifts modulate STIM1-dependent gene expression in Jurkat T cells. Therefore, temperature is an important regulator of STIM1 function.

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: STIM1-Orai1–mediated Ca2+ influx in response to heating.
Figure 2: Temperature effects on CRAC channel–dependent gene expression.
Figure 3: Heat-induced STIM1 clustering.
Figure 4: The STIM1 K-domain is essential for heat-induced STIM1 clustering.
Figure 5: Temperature effects on STIM1-Orai1–mediated ICRAC and STIM1-Orai1 functional coupling.
Figure 6: Heat disrupts store depletion–induced puncta in GFP-STIM1-deltaK–Orai1 cotransfected HeLa cells.

Similar content being viewed by others

References

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

    Article  CAS  Google Scholar 

  2. Hogan, P.G., Lewis, R.S. & Rao, A. Molecular basis of calcium signaling in lymphocytes: STIM and ORAI. Annu. Rev. Immunol. 28, 491–533 (2010).

    Article  CAS  Google Scholar 

  3. Oh-hora, M. & Rao, A. Calcium signaling in lymphocytes. Curr. Opin. Immunol. 20, 250–258 (2008).

    Article  CAS  Google Scholar 

  4. Vig, M. & Kinet, J.P. Calcium signaling in immune cells. Nat. Immunol. 10, 21–27 (2009).

    Article  CAS  Google Scholar 

  5. Feske, S., Picard, C. & Fischer, A. Immunodeficiency due to mutations in ORAI1 and STIM1. Clin. Immunol. 135, 169–182 (2010).

    Article  CAS  Google Scholar 

  6. Putney, J.W. Jr. A model for receptor-regulated calcium entry. Cell Calcium 7, 1–12 (1986).

    Article  CAS  Google Scholar 

  7. Lewis, R.S. The molecular choreography of a store-operated calcium channel. Nature 446, 284–287 (2007).

    Article  CAS  Google Scholar 

  8. Cahalan, M.D. STIMulating store-operated Ca(2+) entry. Nat. Cell Biol. 11, 669–677 (2009).

    Article  CAS  Google Scholar 

  9. 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 

  10. 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 

  11. 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 

  12. Luik, R.M., Wang, B., Prakriya, M., Wu, M.M. & Lewis, R.S. Oligomerization of STIM1 couples ER calcium depletion to CRAC channel activation. Nature 454, 538–542 (2008).

    Article  CAS  Google Scholar 

  13. Stathopulos, P.B., Zheng, L., Li, G.Y., Plevin, M.J. & Ikura, M. Structural and mechanistic insights into STIM1-mediated initiation of store-operated calcium entry. Cell 135, 110–122 (2008).

    Article  CAS  Google Scholar 

  14. Liou, J., Fivaz, M., Inoue, T. & Meyer, T. Live-cell imaging reveals sequential oligomerization and local plasma membrane targeting of stromal interaction molecule 1 after Ca2+ store depletion. Proc. Natl. Acad. Sci. USA 104, 9301–9306 (2007).

    Article  CAS  Google Scholar 

  15. Yuan, J.P. et al. SOAR and the polybasic STIM1 domains gate and regulate Orai channels. Nat. Cell Biol. 11, 337–343 (2009).

    Article  CAS  Google Scholar 

  16. Park, C.Y. et al. STIM1 clusters and activates CRAC channels via direct binding of a cytosolic domain to Orai1. Cell 136, 876–890 (2009).

    Article  CAS  Google Scholar 

  17. Muik, M. et al. A cytosolic homomerization and a modulatory domain within STIM1 C terminus determine coupling to ORAI1 channels. J. Biol. Chem. 284, 8421–8426 (2009).

    Article  CAS  Google Scholar 

  18. Lederman, H.M., Brill, C.R. & Murphy, P.A. Interleukin 1-driven secretion of interleukin 2 is highly temperature-dependent. J. Immunol. 138, 3808–3811 (1987).

    CAS  PubMed  Google Scholar 

  19. Hanson, D.F., Murphy, P.A., Silicano, R. & Shin, H.S. The effect of temperature on the activation of thymocytes by interleukins I and II. J. Immunol. 130, 216–221 (1983).

    CAS  PubMed  Google Scholar 

  20. Hanson, D.F. Fever and the immune response. The effects of physiological temperatures on primary murine splenic T-cell responses in vitro. J. Immunol. 151, 436–448 (1993).

    CAS  PubMed  Google Scholar 

  21. Gern, J.E., Jayman, J.R., Goldberg, L.I., Murphy, P.A. & Lederman, H.M. Temperature is a powerful promoter of interleukin 2 transcription. Cytokine 3, 389–397 (1991).

    Article  CAS  Google Scholar 

  22. Hanson, D.F. Fever, temperature, and the immune response. Ann. NY Acad. Sci. 813, 453–464 (1997).

    Article  CAS  Google Scholar 

  23. Dhaka, A., Viswanath, V. & Patapoutian, A. Trp ion channels and temperature sensation. Annu. Rev. Neurosci. 29, 135–161 (2006).

    Article  CAS  Google Scholar 

  24. Basbaum, A.I., Bautista, D.M., Scherrer, G. & Julius, D. Cellular and molecular mechanisms of pain. Cell 139, 267–284 (2009).

    Article  CAS  Google Scholar 

  25. Yuan, J.P., Zeng, W., Huang, G.N., Worley, P.F. & Muallem, S. STIM1 heteromultimerizes TRPC channels to determine their function as store-operated channels. Nat. Cell Biol. 9, 636–645 (2007).

    Article  CAS  Google Scholar 

  26. DeHaven, W.I. et al. TRPC channels function independently of STIM1 and Orai1. J. Physiol. (Lond.) 587, 2275–2298 (2009).

    Article  CAS  Google Scholar 

  27. Sun, L., Chen, S., Jiang, J., Xie, Y. & Yu, C. Compounds for inflammation and immune-related uses. World Intellectual Property Organization patent number WO/2006/081391 (2006).

  28. Oh-Hora, M. et al. Dual functions for the endoplasmic reticulum calcium sensors STIM1 and STIM2 in T cell activation and tolerance. Nat. Immunol. 9, 432–443 (2008).

    Article  CAS  Google Scholar 

  29. Moran, U., Phillips, R. & Milo, R. SnapShot: key numbers in biology. Cell 141, 1262–1262e.1 (2010).

    Article  Google Scholar 

  30. Peier, A.M. et al. A heat-sensitive TRP channel expressed in keratinocytes. Science 296, 2046–2049 (2002).

    Article  CAS  Google Scholar 

  31. Paltauf-Doburzynska, J. & Graier, W.F. Temperature dependence of agonist-stimulated Ca2+ signaling in cultured endothelial cells. Cell Calcium 21, 43–51 (1997).

    Article  CAS  Google Scholar 

  32. Oliver, A.E., Baker, G.A., Fugate, R.D., Tablin, F. & Crowe, J.H. Effects of temperature on calcium-sensitive fluorescent probes. Biophys. J. 78, 2116–2126 (2000).

    Article  CAS  Google Scholar 

  33. Mercer, J.C. et al. Large store-operated calcium selective currents due to co-expression of Orai1 or Orai2 with the intracellular calcium sensor, Stim1. J. Biol. Chem. 281, 24979–24990 (2006).

    Article  CAS  Google Scholar 

  34. Stathopulos, P.B., Li, G.Y., Plevin, M.J., Ames, J.B. & Ikura, M. Stored Ca2+ depletion-induced oligomerization of stromal interaction molecule 1 (STIM1) via the EF-SAM region: An initiation mechanism for capacitive Ca2+ entry. J. Biol. Chem. 281, 35855–35862 (2006).

    Article  CAS  Google Scholar 

  35. Zheng, L., Stathopulos, P.B., Li, G.Y. & Ikura, M. Biophysical characterization of the EF-hand and SAM domain containing Ca2+ sensory region of STIM1 and STIM2. Biochem. Biophys. Res. Commun. 369, 240–246 (2008).

    Article  CAS  Google Scholar 

  36. Huang, G.N. et al. STIM1 carboxyl-terminus activates native SOC, I(crac) and TRPC1 channels. Nat. Cell Biol. 8, 1003–1010 (2006).

    Article  CAS  Google Scholar 

  37. Wang, Y. et al. STIM protein coupling in the activation of Orai channels. Proc. Natl. Acad. Sci. USA 106, 7391–7396 (2009).

    Article  CAS  Google Scholar 

  38. Korzeniowski, M.K., Manjarres, I.M., Varnai, P. & Balla, T. Activation of STIM1-Orai1 involves an intramolecular switching mechanism. Sci. Signal. 3, ra82 (2010).

    Article  CAS  Google Scholar 

  39. Hawkins, B.J. et al. S-glutathionylation activates STIM1 and alters mitochondrial homeostasis. J. Cell Biol. 190, 391–405 (2010).

    Article  CAS  Google Scholar 

  40. Bandell, M., Macpherson, L.J. & Patapoutian, A. From chills to chilis: mechanisms for thermosensation and chemesthesis via thermoTRPs. Curr. Opin. Neurobiol. 17, 490–497 (2007).

    Article  CAS  Google Scholar 

  41. Varga-Szabo, D., Braun, A. & Nieswandt, B. Calcium signaling in platelets. J. Thromb. Haemost. 7, 1057–1066 (2009).

    Article  CAS  Google Scholar 

  42. Stiber, J. et al. STIM1 signalling controls store-operated calcium entry required for development and contractile function in skeletal muscle. Nat. Cell Biol. 10, 688–697 (2008).

    Article  CAS  Google Scholar 

  43. Gwack, Y. et al. Hair loss and defective T- and B-cell function in mice lacking ORAI1. Mol. Cell. Biol. 28, 5209–5222 (2008).

    Article  CAS  Google Scholar 

  44. Varga-Szabo, D. et al. The calcium sensor STIM1 is an essential mediator of arterial thrombosis and ischemic brain infarction. J. Exp. Med. 205, 1583–1591 (2008).

    Article  CAS  Google Scholar 

  45. Kenny, G.P. et al. Muscle temperature transients before, during, and after exercise measured using an intramuscular multisensor probe. J. Appl. Physiol. 94, 2350–2357 (2003).

    Article  CAS  Google Scholar 

  46. Xiao, B. et al. Identification of transmembrane domain 5 as a critical molecular determinant of menthol sensitivity in mammalian TRPA1 channels. J. Neurosci. 28, 9640–9651 (2008).

    Article  CAS  Google Scholar 

  47. Grandl, J. et al. Pore region of TRPV3 ion channel is specifically required for heat activation. Nat. Neurosci. 11, 1007–1013 (2008).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank R.Y. Tsien (University of California, San Diego), P. Shultz (The Scripps Research Institute), S.-S. Tian (Genomics Institute of the Novartis Research Foundation, GNF), A. Parker (GNF), D. Tully (GNF) and S.F. Pan (GNF) for providing reagents; E. Rodrigo, E. Peters, J. Liu, K. Spencer, T. Earley, D. Li and J. Mitsios for experimental help; M. Schmidt for providing advice on GFP-STIM1 puncta analysis; C. Schmedt, M. Cooke, D. Geurini, S.-S. Tian and S. Sanford for discussions; and N. Hong and J. Grandl for reading the manuscript. This research was supported by US National Institutes of Health grants DE016927 and NS046303 and by the Novartis Research Foundation. B.X. is a postdoctoral fellowship recipient from Canadian Institutes of Health Research, Alberta Heritage Foundation for Medical Research and American Heart Association. B.C. is a postdoctoral fellowship recipient from American Heart Association.

Author information

Authors and Affiliations

Authors

Contributions

B.X. performed the bulk of the studies. B.C. performed all the electrophysiological studies. J.M. performed quantitative real time–PCR and molecular cloning experiments. B.X., B.C. and A.P. designed the experiments and wrote the paper. All authors read and discussed the paper.

Corresponding author

Correspondence to Ardem Patapoutian.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Methods and Supplementary Figures 1–5 (PDF 6519 kb)

Supplementary Video 1

Temperature-dependent changes of GFP-STIM1 puncta and Fura2 ratio in HeLa cells transfected with GFP-STIM1. (MPG 7527 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xiao, B., Coste, B., Mathur, J. et al. Temperature-dependent STIM1 activation induces Ca2+ influx and modulates gene expression. Nat Chem Biol 7, 351–358 (2011). https://doi.org/10.1038/nchembio.558

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.558

This article is cited by

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