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Dysfunction of store-operated calcium channel in muscle cells lacking mg29

Nature Cell Biology volume 4, pages 379–383 (2002)Cite this article

Abstract

The store-operated calcium channel (SOC) located in the plasma membrane (PM) mediates capacitative entry of extracellular calcium after depletion of intracellular calcium stores in the endoplasmic or sarcoplasmic reticulum (ER/SR)1,2. An intimate interaction between the PM and the ER/SR is essential for the operation of this calcium signalling pathway3,4,5. Mitsugumin 29 (MG29) is a synaptophysin-family-related protein located in the junction between the PM and SR of skeletal muscle6,7. Here, we identify SOC in skeletal muscle and characterise its regulation by MG29 and the ryanodine receptor (RyR) located in the SR. Targeted deletion of mg29 alters the junctional membrane structure, causes severe dysfunction of SOC and SR calcium homeostasis and increases the susceptibility of muscle to fatigue stimulation8. Severe dysfunction of SOC is also identified in muscle cells lacking both type 1 and type 3 RyRs, indicating that SOC activation requires an intact interaction between the PM and the SR, and is linked to conformational changes of RyRs. Whereas defective SOC seems to be inconsequential to short-term excitation–contraction coupling, the slow cumulative calcium entry through SOC is crucial for long-term calcium homeostasis, such that reduced SOC activity exaggerates muscle fatigue under conditions of intensive exercise.

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Figure 1: Defective movement of calcium across the PM in skeletal muscle lacking MG29.
Figure 2: Dysfunction of SOC in mg29−/− myotubes.
Figure 3: RyR-mediated activation of SOC in skeletal muscle.
Figure 4: Inhibition of SOC activity in skeletal muscle by 2-APB.
Figure 5: The effects of SKF-96365 and extracellular calcium on the fatigue sensitivity of soleus muscles.

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Acknowledgements

We thank E. Rios, E. Lakatta, N. Partridge, J. Parness and C. Sciortino for helpful comments on the manuscript. We also appreciate the generous help and support from M. Bhat and D. Damron for the Fura-2 calcium studies. This work was supported by grants from the National Institutes of Health and the American Heart Association.

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Authors and Affiliations

  1. Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, 08854, NJ, USA

    Zui Pan, Ramakrishnan Y. Nagaraj & Jianjie Ma

  2. Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, 21224, MD, USA

    Dongmei Yang & Heping Cheng

  3. National Laboratory of Biomembrane and Membrane Biotechnology, College of Life Sciences, Peking University, Beijing, 100871, China

    Dongmei Yang

  4. Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, OH 44106, USA

    Thomas A. Nosek

  5. Department of Biochemistry, Tohoku University Graduate School of Medicine and CREST, Japan Science and Technology Corporation, Sendai, 980-8575, Japan

    Miyuki Nishi & Hiroshi Takeshima

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  1. Zui Pan
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Pan, Z., Yang, D., Nagaraj, R. et al. Dysfunction of store-operated calcium channel in muscle cells lacking mg29. Nat Cell Biol 4, 379–383 (2002). https://doi.org/10.1038/ncb788

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