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Excitation-contraction uncoupling and muscular degeneration in mice lacking functional skeletal muscle ryanodine-receptor gene

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Abstract

CONTRACTION of skeletal muscle is triggered by the release of Ca2+ from the sarcoplasmic reticulum (SR) after depolarization of transverse tubules1,2. The ryanodine receptor exists as a 'foot' protein in the junctional gap between the sarcoplasmic reticulum and the transverse tubule in skeletal muscle, and is proposed to function as a calcium-release channel during excitation-contraction (E-C) coupling3–6. Previous complementary DNA-cloning studies have defined three distinct subtypes of the ryanodine receptor in mammalian tissues, namely skeletal muscle, cardiac and brain types7–12. We report here mice with a targeted mutation in the skeletal muscle ryanodine receptor gene. Mice homozygous for the mutation die perinatally with gross abnormalities of the skeletal muscle. The contractile response to electrical stimulation under physiological conditions is totally abolished in the mutant muscle, although ryanodine receptors other than the skeletal-muscle type seem to exist because the response to caffeine is retained. Our results show that the skeletal muscle ryanodine receptor is essential for both muscular maturation and E-C coupling, and also imply that the function of the skeletal muscle ryanodine receptor during E-C coupling cannot be substituted by other subtypes of the receptor.

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  1. Hiroshi Takeshima: To whom correspondence should be addressed at:

Authors and Affiliations

  1. International Institute for Advanced Studies, Shimazdu N-80, 1 Nishinokyo-Kuwahara-cho, Kyoto, 604, Japan

    Hiroshi Takeshima & Miyuki Nishi

  2. Department of Pharmacology, Faculty of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113, Japan

    Masamitsu lino

  3. Department of Physiology, National Institute of Fitness and Sports, 1 Shiromizu, Kanoya, Kagoshima, 891-23, Japan

    Hiroaki Takekura

  4. Department of Cell Biology, Cancer Institute, 1-37-1 Kami-lkebukuro, Toshima-ku, Tokyo, 170, Japan

    Miyuki Nishi, Junko Kuno, Osamu Minowa, Hiroshi Takano & Tetsuo Noda

  5. Department of Neurochemistry, Tokyo Institute of Psychiatry, 2-1-8 Kamikitasawa, Setagaya-ku, Tokyo, 156, Japan

    Hiroshi Takeshima

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  1. Hiroshi Takeshima
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  8. Tetsuo Noda
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Takeshima, H., lino, M., Takekura, H. et al. Excitation-contraction uncoupling and muscular degeneration in mice lacking functional skeletal muscle ryanodine-receptor gene. Nature 369, 556–559 (1994). https://doi.org/10.1038/369556a0

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