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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References
Endo, M. Physiol. Rev. 57, 71–108 (1977).
Martonosi, A. N. Physiol. Rev. 64, 1240–1320 (1984).
Fleischer, S. & Inui, M. A. Rev. Biophys. biophys. Chem. 18, 333–364 (1989).
McPherson, P. S. & Campbell, K. P. J. biol. Chem. 268, 13765–13768 (1993).
Lai, F. A., Erickson, H. P., Rousseau, E., Liu, Q-Y. & Meissner, G. Nature 331, 315–319 (1988).
Block, B. A., Imagawa, T., Campbell, K. P. & Franzini-Armstrong, C. J. Cell Biol. 107, 2587–2600 (1988).
Takeshima, H. et al. Nature 339, 439–445 (1989).
Zorzato, F. et al. J. biol. Chem. 265, 2244–2256 (1990).
Otsu, K. et al. J. biol. Chem. 265, 13472–13483 (1990).
Nakai, J. et al. FEBS Lett. 271, 169–177 (1990).
Giannini, G., Clementi, E., Ceci, R., Marziali, G. & Sorrentino, V. Science 257, 91–94 (1992).
Hakamata, Y., Nakai, J., Takeshima, H. & Imoto, K. FEBS Lett. 312, 229–235 (1992).
Li, E., Bestor, T. H. & Jaenisch, R. Cell 69, 915–926 (1992).
Hasty, P. et al. Nature 364, 501–506 (1993).
Nabeshima, Y. et al. Nature 364, 532–535 (1993).
Gluecksohn-Waelsch, S. Science 142, 1269–1276 (1963).
Pai, A. C. Devl Biol. 11, 82–92 (1965).
Klaus, M. M., Scordilis, S. P., Rapalus, J. M., Briggs, R. T. & Powell, J. A. Devl Biol. 99, 152–165 (1983).
Beam, K. G., Knudson, C. M. & Powell, J. A. Nature 320, 168–170 (1986).
Chaudhari, N. J. biol. Chem. 267, 25636–25639 (1992).
Pai, A. C. Devl Biol. 11, 93–109 (1965).
Rios, E. & Brum, G. Nature 325, 717–720 (1987).
Tanabe, T., Beam, K. G., Powell, J. A. & Numa, S. Nature 336, 134–139 (1988).
Numa, S. et al. Cold Spring Harb. Symp. q. Biol. 40, 1–7 (1990).
Braum, T., Rudnicki, M. A., Arnold, H-H. & Jaenisch, R. Cell 71, 369–382 (1992).
Sanger, F., Nicklen, S. & Coulson, A. R. Proc. natn. Acad. Sci. U.S.A. 74, 5463–5467 (1977).
Rudnicki, M. A., Braun, T., Hinuma, S. & Jaenisch, R. Cell 71, 383–390 (1992).
Southern, E. M. Meth. Enzym. 68, 152–176 (1979).
Mansour, A. P. & Bradley, A. Cell 62, 1073–1085 (1990).
Saiki, R. K. et al. Science 239, 487–491 (1988).
Chirgwin, J. M., Przybyla, A. E., MacDonald, R. J. & Rutter, W. J. Biochemistry 18, 5294–5299 (1979).
Mishina, M. et al. Nature 321, 406–411 (1986).
Saito, A., Seiler, S., Chu, A. & Fleischer, S. J. Cell Biol. 103, 741–753 (1986).
Takeshima, H., Nishimura, S., Nishi, M., Ikeda, M. & Sugimoto, T. FEBS Lett. 322, 105–110 (1993).
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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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DOI: https://doi.org/10.1038/369556a0
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