EXCITATION-CONTRACTION UNCOUPLING AND MUSCULAR DEGENERATION IN MICE LACKING FUNCTIONAL SKELETAL-MUSCLE RYANODINE-RECEPTOR GENE
EXCITATION-CONTRACTION UNCOUPLING AND MUSCULAR DEGENERATION IN MICE LACKING FUNCTIONAL SKELETAL-MUSCLE RYANODINE-RECEPTOR GENE
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DOI：
10.1038/369556a0
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发表时间：
1994-06-16
期刊：
影响因子：
64.8
通讯作者：
NODA, T
中科院分区：
文献类型：
--
作者：
TAKESHIMA, H;IINO, M;NODA, T
横小管去极化后，肌浆网（SR）释放的Ca 2+触发骨骼肌收缩（1，2）。兰尼碱受体作为骨骼肌肌浆网和横小管之间的连接间隙中的“足”蛋白存在，并被认为在兴奋-收缩（E-C）偶联过程中起钙释放通道的作用（3-6）。先前的互补DNA克隆研究已经确定了哺乳动物组织中兰尼碱受体的三种不同亚型，即骨骼肌、心脏和脑型（7-12）。我们在这里报告小鼠骨骼肌兰尼碱受体基因的靶向突变。突变纯合子小鼠围产期死亡，骨骼肌严重异常。在生理条件下的电刺激的收缩反应是完全废除的突变肌肉，虽然Ryanodine受体以外的肌肉类型似乎存在，因为咖啡因的反应被保留。我们的研究结果表明骨骼肌兰尼碱受体是肌肉成熟和E-C偶联所必需的，也意味着骨骼肌兰尼碱受体在E-C偶联过程中的功能不能被其他亚型的受体所取代。
CONTRACTION of skeletal muscle is triggered by the release of Ca2+ from the sarcoplasmic reticulum (SR) after depolarization of transverse tubules(1,2). 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) coupling(3-6). Previous complementary DNA-cloning studies have defined three distinct subtypes of the ryanodine receptor in mammalian tissues, namely skeletal muscle, cardiac and brain types(7-12). 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.