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STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane

Abstract

As the sole Ca2+ entry mechanism in a variety of non-excitable cells, store-operated calcium (SOC) influx is important in Ca2+ signalling and many other cellular processes1,2,3. A calcium-release-activated calcium (CRAC) channel in T lymphocytes is the best-characterized SOC influx channel4,5,6 and is essential to the immune response, sustained activity of CRAC channels being required for gene expression and proliferation7,8,9,10. The molecular identity and the gating mechanism of SOC and CRAC channels have remained elusive. Previously we identified Stim and the mammalian homologue STIM1 as essential components of CRAC channel activation in Drosophila S2 cells and human T lymphocytes11. Here we show that the expression of EF-hand mutants of Stim or STIM1 activates CRAC channels constitutively without changing Ca2+ store content. By immunofluorescence, EM localization and surface biotinylation we show that STIM1 migrates from endoplasmic-reticulum-like sites to the plasma membrane upon depletion of the Ca2+ store. We propose that STIM1 functions as the missing link between Ca2+ store depletion and SOC influx, serving as a Ca2+ sensor that translocates upon store depletion to the plasma membrane to activate CRAC channels.

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Figure 1: Constitutive activation of CRAC channels by expression of EF-hand mutants of Stim or STIM1.
Figure 2: Mutations in EF-hand motif or store depletion induce STIM1 translocation to the plasma membrane.
Figure 3: Subcellular distribution of STIM1 before and after store depletion: immunoelectron microscopy and surface biotinylation.
Figure 4: Models of STIM1 function.

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Acknowledgements

We thank L. Forrest for assistance with cell culture; A. Yeromin, O. Safrina and S. Wei for help with [Ca2+]i imaging; G. Chandy for the use of molecular reagents and laboratory facilities; C. Hughes for providing access to the Amaxa Nucleofector; A. Kolski-Andreaco for the gift of pAc5.1/EGFP; K. Knowlton and D. Summers-Torres from the Department of Medicine, University of California, San Diego for help with deconvolution immunofluorescence microscopy; and P. J. DiGregorio, G. Velicelebi, M. Lioudyno, J. Hall and Y. Li for discussion. Confocal microscopy was performed at the Optical Biology Shared Resource, supported by a Developmental Biology Center and Cancer Center Support Grant at the University of California, Irvine. This work was supported by grants from the National Institutes of Health (to M.D.C. and M.H.E.) and by a fellowship from the Pulmonary Hypertension Association (to Y.Y.).

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Correspondence to Michael D. Cahalan.

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Zhang, S., Yu, Y., Roos, J. 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). https://doi.org/10.1038/nature04147

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