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STIM1 heteromultimerizes TRPC channels to determine their function as store-operated channels

Nature Cell Biology volume 9, pages 636–645 (2007)Cite this article

Abstract

Stromal interacting molecule 1 (STIM1) is a Ca2+ sensor that conveys the Ca2+ load of the endoplasmic reticulum to store-operated channels (SOCs) at the plasma membrane. Here, we report that STIM1 binds TRPC1, TRPC4 and TRPC5 and determines their function as SOCs. Inhibition of STIM1 function inhibits activation of TRPC5 by receptor stimulation, but not by La3+, suggesting that STIM1 is obligatory for activation of TRPC channels by agonists, but STIM1 is not essential for channel function. Through a distinct mechanism, STIM1 also regulates TRPC3 and TRPC6. STIM1 does not bind TRPC3 and TRPC6, and regulates their function indirectly by mediating the heteromultimerization of TRPC3 with TRPC1 and TRPC6 with TRPC4. TRPC7 is not regulated by STIM1. We propose a new definition of SOCs, as channels that are regulated by STIM1 and require the store depletion-mediated clustering of STIM1. By this definition, all TRPC channels, except TRPC7, function as SOCs.

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Figure 1: Regulation of TRPC3 by STIM1.
Figure 2: STIM1-mediated interaction of TRPC3 with TRPC1.
Figure 3: Regulation of TRPC3 by STIM1 requires TRPC1.
Figure 4: Regulation of TRPC6 by STIM1.
Figure 5: Interaction of TRPC6 with TRPC4 mediates regulation of TRPC6 by STIM1.
Figure 6: STIM1 regulates TRPC5 but it is not obligatory for channel function.
Figure 7: TRPC7 is not regulated by STIM1.

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Acknowledgements

We thank Y Mori for GFP–TRPC5, TRPC6 and TRPC7 plasmids. This work was supported in part by grant BGIA 06651924 from the Texas American Heart Association to W.Z., National Institutes of Health Grants DE12309 and DK38938 and the Ruth S. Harrell Professorship in Medical Research to S.M. and by the National Institute on Drug Abuse (NIDA; DA00266, DA10309) and the National Institute of Mental Health (NIMH; MH068830) to P.F.W.

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Author notes

  1. Joseph P. Yuan and Weizhong Zeng: These authors contributed equally to this work.

Authors and Affiliations

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

    Joseph P. Yuan, Weizhong Zeng & Shmuel Muallem

  2. Department of Neuroscience and Neurology, The Johns Hopkins University School of Medicine, Baltimore, 21205, MD, USA

    Guo N. Huang & Paul F. Worley

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

    Paul F. Worley

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  1. Joseph P. Yuan
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Contributions

J.P.Y, W.Z and G.N.H performed and analysed the experiments. PF.W. and S.M. planned and analysed the experiments. All authors contributed to writing the manuscript.

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Correspondence to Paul F. Worley or Shmuel Muallem.

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Yuan, J., Zeng, W., Huang, G. et al. STIM1 heteromultimerizes TRPC channels to determine their function as store-operated channels. Nat Cell Biol 9, 636–645 (2007). https://doi.org/10.1038/ncb1590

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