Molecular biological studies of ryanodine receptor/calcium release channel

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The aim of this research is elucidating physiological functions of teh ryanodine receptor/calcium ralease channel in a whole animallevel. Thus, we first tried to find or generate mutant animals in the ryanodine receptor gene. Because so many mutants are known in fruit fly system, we analyzed a ryanodine receptor gene in Drosophila melanogaster and the chromosomal mapping was done (FEBS) Lett. 337,81) ; however, no mutant is known at the located chromosomal position. Then, we tried to prepare mutnat mice lacking the skeletal muscle ryanodine receptor using embyonic stem cells. In the first analysis of the generated mutant mice, we showed that the skeletal muscle ryanodine receptor is an essential molecule for muscle maturation and excitation-contraction coupling (Nature 369,556). An electron-microscopy found triad juctions with a narrow size between transverse-tuble and sarcoplasmi reticulum membranes in the mutnat muscle, indicationg that the skeletal muscle ryanodine receptor determines the size between the membranes but is not essential for generation of the junction (Proc.Natl.Acad.Sci.USA.92,3391). Moreover, we found expression of the brain-type of ryanodine receptor in mutant muscle, and revealedits pharmoacological properties accompanying inability to contribute skeletal muscle exicitation-conrtraction couplina (EMBO J.14,2999).In summary, we defined the phisiological function of the skeletal muscle ryanodine receptor by generation and analysis of knockout mice, and showed the differential role between ryanodine receptor shbtypes.