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

Nature Chemical Biology volume 7, pages 351–358 (2011)Cite this article

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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.

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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.

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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.

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Affiliations

  1. Department of Cell Biology, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California, USA

    Bailong Xiao, Bertrand Coste & Ardem Patapoutian

  2. Genomics Institute of the Novartis Research Foundation, San Diego, California, USA

    Jayanti Mathur & Ardem Patapoutian

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  1. Bailong Xiao
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  2. Bertrand Coste
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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.

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Correspondence to Ardem Patapoutian.

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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)

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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

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