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| The EMBO Journal
(1998) 17, 3309–3316, doi:10.1093/emboj/17.12.3309 |
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| Embryonic lethality and abnormal cardiac myocytes in mice lacking ryanodine receptor type 2 |
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| Hiroshi Takeshima1, 2, Shinji Komazaki3, Kenzo Hirose1, 2, Miyuki Nishi1, 2, Tetsuo Noda2, 4 and Masamitsu Iino1, 2 |
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1 Department of Pharmacology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan 2 CREST, Japan Science and Technology Corporation, Saitama Medical School, Moroyama-machi, Saitama 350-01, Japan 3 Department of Anatomy, Saitama Medical School, Moroyama-machi, Saitama 350-01, Japan 4 Department of Cell Biology, Cancer Institute, Kami-Ikebukuro, Toshima-ku, Tokyo 170, Japan To whom correspondence should be addressed Hiroshi Takeshima, takeshim@m.u-tokyo.ac.jp Received 5 March 1998; Revised 15 April 1998; Accepted 16 April 1998. |
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| Abstract |
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| The ryanodine receptor type 2 (RyR-2) functions as a Ca2+-induced Ca2+ release (CICR) channel on intracellular Ca2+ stores and is distributed in most excitable cells with the exception of skeletal muscle cells. RyR-2 is abundantly expressed in cardiac muscle cells and is thought to mediate Ca2+ release triggered by Ca2+ influx through the voltage-gated Ca2+ channel to constitute the cardiac type of excitation–contraction (E–C) coupling. Here we report on mutant mice lacking RyR-2. The mutant mice died at approximately embryonic day (E) 10 with morphological abnormalities in the heart tube. Prior to embryonic death, large vacuolate sarcoplasmic reticulum (SR) and structurally abnormal mitochondria began to develop in the mutant cardiac myocytes, and the vacuolate SR appeared to contain high concentrations of Ca2+. Fluorometric Ca2+ measurements showed that a Ca2+ transient evoked by caffeine, an activator of RyRs, was abolished in the mutant cardiac myocytes. However, both mutant and control hearts showed spontaneous rhythmic contractions at E9.5. Moreover, treatment with ryanodine, which locks RyR channels in their open state, did not exert a major effect on spontaneous Ca2+ transients in control cardiac myocytes at E9.5–11.5. These results suggest no essential contribution of the RyR-2 to E–C coupling in cardiac myocytes during early embryonic stages. Our results from the mutant mice indicate that the major role of RyR-2 is not in E–C coupling as the CICR channel in embryonic cardiac myocytes but it is absolutely required for cellular Ca2+ homeostasis most probably as a major Ca2+ leak channel to maintain the developing SR. |
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| Keywords: Ca2+ store, caffeine, gene targeting, ryanodine, ryanodine receptor |
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