α1-syntrophin gene disruption results in the absence of neuronal-type nitric-oxide synthase at the sarcolemma but does not induce muscle degeneration
α1-syntrophin gene disruption results in the absence of neuronal-type nitric-oxide synthase at the sarcolemma but does not induce muscle degeneration
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DOI：
10.1074/jbc.274.4.2193
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发表时间：
1999-01-22
影响因子：
4.8
通讯作者：
Takeda, S
中科院分区：
文献类型：
--
作者：
Kameya, S;Miyagoe, Y;Takeda, S
α1-肌营养不良蛋白是肌营养不良蛋白相关蛋白家族的成员，在肌膜和神经肌肉连接处强烈表达。所有三种肌营养蛋白亚型都有一个 PDZ 结构域，该结构域似乎参与质膜上的蛋白质-蛋白质相互作用。此外，α1-Syntropin 还被证明在体外通过 PDZ 结构域与神经元一氧化氮合酶 (nNOS) 相关。这些观察结果表明，α1-肌营养不良蛋白可能作为一种模块化衔接蛋白，可以将 nNOS 或其他信号酶与肌膜肌营养不良蛋白复合物连接起来。在肌膜中，nNOS 调节活性自由基的稳态，并可能导致杜氏肌营养不良等肌肉疾病中肌肉蛋白的氧化损伤。在这项研究中，我们培育了 α1-肌营养蛋白基因敲除小鼠，以阐明骨骼肌中 α1-肌营养蛋白和 nNOS 之间的相互作用。我们观察到，通常在肌膜中表达的 nNOS 在很大程度上不存在于肌膜中，但在敲除小鼠的细胞质中大量保留。尽管 nNOS 的分布发生了改变，但基因敲除小鼠的骨骼肌没有表现出明显的组织学变化。我们还发现基因敲除小鼠的肌肉收缩特性没有受到影响。
alpha 1-Syntrophin is a member of the family of dystrophin-associated proteins and is strongly expressed in the sarcolemma and the neuromuscalar junctions. All three syntrophin isoforms have a PDZ domain that appears to participate in protein-protein interactions at the plasma membrane. alpha 1-Syntrophin has additionally been shown to associate with neuronal nitric-oxide synthase (nNOS) through PDZ domains in vitro. These observations suggest that alpha 1-syntrophin may work as a modular adaptor protein that can link nNOS or other signaling enzyme to the sarcolemmal dystrophin complex. In the sarcolemma, nNOS regulates the homeostasis of reactive free radical species and may contribute to the oxidative damage to muscle protein in muscle disease such as Duchenne muscular dystrophy. In this study, we generated alpha 1-syntrophin knockout mice to clarify the interaction between alpha 1-syntrophin and nNOS in the skeletal muscle. We observed that nNOS, normally expressed in the sarcolemma, was largely absent from the sarcolemma, but considerably remained in the cytosol of the knock-out mice. Even though the distribution of nNOS was altered, the knock-out mice displayed no gross histological changes in the skeletal muscle. We also discovered that muscle contractile properties have not been influenced in the knock-out mice.