Nav1.4 deregulation in dystrophic skeletal muscle leads to Na+ overload and enhanced cell death.
Nav1.4 deregulation in dystrophic skeletal muscle leads to Na+ overload and enhanced cell death.
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NAV1.4营养不良骨骼肌的放松管制导致NA+超负荷并增强细胞死亡。
DOI：
10.1085/jgp.200810024
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发表时间：
2008-08
影响因子：
3.8
通讯作者：
Ruegg, Urs T.
中科院分区：
文献类型：
--
作者：
Hirn, Carole;Shapovalov, George;Petermann, Olivier;Roulet, Emmanuelle;Ruegg, Urs T.
杜氏肌营养不良症（DMD）是一种遗传性退行性疾病，表现为缺乏营养不良蛋白（一种结构细胞骨架蛋白），导致肌肉变性和通过呼吸和心肌衰竭而早期死亡。虽然mdx小鼠（DMD的动物模型）肌肉中胞质Ca2+浓度的升高已被广泛记录，但对引起Na+浓度改变的机制知之甚少。本研究表明，骨骼肌中电压门控钠通道Nav1.4亚型代表了肌肉中90%以上的电压门控钠通道，在mdx小鼠肌肉中发现的异常高Na+浓度的发展中起着重要作用。肌营养不良蛋白的缺失改变了Nav1.4的表达水平和门控特性，导致肌膜下Na+浓度升高。此外，Nav1.4在mdx肌肉中的分布发生改变，同时与肌营养不良蛋白相关蛋白之一syntrophin α-1保持共定位，这表明syntrophin是肌营养不良蛋白与Nav1.4之间的重要联系。此外，我们发现这些Nav1.4门通特性的改变和Na+浓度的增加与mdx纤维中细胞死亡的增加密切相关，并且细胞死亡和Na+过载都可以通过3nm河豚毒素（一种特定的Nav1.4阻滞剂）逆转。
Duchenne muscular dystrophy (DMD) is a hereditary degenerative disease manifested by the absence of dystrophin, a structural, cytoskeletal protein, leading to muscle degeneration and early death through respiratory and cardiac muscle failure. Whereas the rise of cytosolic Ca2+ concentrations in muscles of mdx mouse, an animal model of DMD, has been extensively documented, little is known about the mechanisms causing alterations in Na+ concentrations. Here we show that the skeletal muscle isoform of the voltage-gated sodium channel, Nav1.4, which represents over 90% of voltage-gated sodium channels in muscle, plays an important role in development of abnormally high Na+ concentrations found in muscle from mdx mice. The absence of dystrophin modifies the expression level and gating properties of Nav1.4, leading to an increased Na+ concentration under the sarcolemma. Moreover, the distribution of Nav1.4 is altered in mdx muscle while maintaining the colocalization with one of the dystrophin-associated proteins, syntrophin α-1, thus suggesting that syntrophin is an important linker between dystrophin and Nav1.4. Additionally, we show that these modifications of Nav1.4 gating properties and increased Na+ concentrations are strongly correlated with increased cell death in mdx fibers and that both cell death and Na+ overload can be reversed by 3 nM tetrodotoxin, a specific Nav1.4 blocker.
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影响因子：
56.9
作者：
FONG, P;TURNER, PR;STEINHARDT, RA
通讯作者：
STEINHARDT, RA
影响因子：
20.1
作者：
Gavillet, Bruno;Rougier, Jean-Sebastien;Abriel, Hugues
通讯作者：
Abriel, Hugues
影响因子：
5.5
作者：
HEAD, SI
通讯作者：
HEAD, SI
影响因子：
5.5
作者：
Yeung, EW;Head, SI;Allen, DG
通讯作者：
Allen, DG
影响因子：
7.8
作者：
Williams, M W;Bloch, R J
通讯作者：
Bloch, R J