Hypernitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle.
Hypernitrosylated ryanodine receptor calcium release channels are leaky in dystrophic muscle.
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作者：
杜氏肌营养不良症（DMD）的特征是进行性肌无力和早期死亡导致的肌营养不良蛋白缺乏。肌营养不良蛋白的缺失导致大的肌营养不良蛋白糖蛋白复合物（DGC）的破坏，导致损伤肌肉细胞的病理性钙（Ca 2+）依赖性信号。我们已经确定了肌浆网（SR）钙释放通道/ryanodine受体（RyR 1）在mdx小鼠模型的肌营养不良，可能有助于改变钙稳态营养不良肌肉的结构和功能缺陷。从mdx骨骼肌中分离的RyR 1表现出与肌肉营养不良变化一致的S-亚硝基化的年龄依赖性增加。RyR 1 S-亚硝基化耗尽FKBP 12的通道复合物（或钙通道稳定结合蛋白的“钙稳定蛋白1”），导致“渗漏”通道。使用S107（一种结合RyR 1通道并增强钙稳定蛋白1与亚硝基化通道结合亲和力的化合物）防止RyR 1消耗钙稳定蛋白1，抑制SR Ca 2+泄漏，减少肌肉损伤的生化和组织学证据，改善肌肉功能并增加mdx小鼠的运动表现。因此，由于通道的S-亚硝基化和钙稳定蛋白1缺失，通过RyR 1的SR Ca 2+泄漏可能导致肌营养不良症中的肌无力，并且预防RyR 1介导的SR Ca 2+泄漏可能提供一种新的治疗方法。
Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness and early death resulting from dystrophin deficiency. Loss of dystrophin results in disruption of a large dystrophin glycoprotein complex (DGC) leading to pathologic calcium (Ca2+)-dependent signals that damage muscle cells. We have identified a structural and functional defect in the sarcoplasmic reticulum (SR) Ca2+ release channel/ryanodine receptor (RyR1) in the mdx mouse model of muscular dystrophy that may contribute to altered Ca2+ homeostasis in dystrophic muscles. RyR1 isolated from mdx skeletal muscle exhibited an age-dependent increase in S-nitrosylation coincident with dystrophic changes in the muscle. RyR1 S-nitrosylation depleted the channel complex of FKBP12 (or “calstabin1” for calcium channel stabilizing binding protein) resulting in “leaky” channels. Preventing calstabin1 depletion from RyR1 using S107, a compound that binds to the RyR1 channel and enhances the binding affinity of calstabin1 to the nitrosylated channel, inhibited SR Ca2+ leak, reduced biochemical and histologic evidence of muscle damage, improved muscle function and increased exercise performance in mdx mice. Thus, SR Ca2+ leak via RyR1 due to S-nitrosylation of the channel and calstabin1 depletion likely contributes to muscle weakness in muscular dystrophy and preventing the RyR1-mediated SR Ca2+ leak may provide a novel therapeutic approach.
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DOI：
10.1073/pnas.93.17.9142
发表时间：
1996-08-20
影响因子：
11.1
作者：
Chang, WJ;Iannaccone, ST;Stull, JT
通讯作者：
Stull, JT
影响因子：
56.9
作者：
FONG, P;TURNER, PR;STEINHARDT, RA
通讯作者：
STEINHARDT, RA
影响因子：
64.5
作者：
BRILLANTES, AMB;ONDRIAS, K;MARKS, AR
通讯作者：
MARKS, AR
影响因子：
56.9
作者：
Marx, SO;Ondrias, K;Marks, AR
通讯作者：
Marks, AR
影响因子：
64.5
作者：
Marx, SO;Reiken, S;Marks, AR
通讯作者：
Marks, AR