Congenital myopathy results from misregulation of a muscle Ca2+ channel by mutant Stac3
Congenital myopathy results from misregulation of a muscle Ca2+ channel by mutant Stac3
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DOI：
10.1073/pnas.1619238114
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发表时间：
2017-01-10
影响因子：
11.1
通讯作者：
Kuwada, John Y.
中科院分区：
文献类型：
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作者：
Linsley, Jeremy W.;Hsu, I-Uen;Kuwada, John Y.
骨骼肌收缩是由兴奋-收缩（EC）偶联过程中释放的Ca 2+增加引起的，EC偶联缺陷与人类肌病有关。EC偶联需要横小管膜上的电压敏感二氢吡啶受体（DHPR）和肌浆网（SR）上的钙释放通道Ryanodine受体1（RyR 1）之间的通信。Stac 3蛋白（SH 3和富含半胱氨酸的结构域3）是EC偶联装置的重要组成部分，人类STAC 3的突变导致衰弱的美洲原住民肌病（NAM），但Stac 3如何作用于DHPR和/或RyR 1的性质尚不清楚。使用电子显微镜，电生理学和斑马鱼肌肉纤维的动态成像，我们发现显着降低DHPR水平，功能和稳定性stac 3突变体。此外，stac 3（NAM）肌纤维表现出增加的咖啡因诱导的Ca 2+释放在广泛的浓度范围内的情况下，改变咖啡因的敏感性，以及增加的Ca 2+在内部存储，这是一致的增加SR腔Ca 2+。这些发现定义了Stac 3在EC偶联和人类疾病中的关键作用。
Skeletalmuscle contractions are initiated by an increase in Ca2+ released during excitation-contraction (EC) coupling, and defects in EC coupling are associated with human myopathies. EC coupling requires communication between voltage-sensing dihydropyridine receptors (DHPRs) in transverse tubule membrane and Ca2+ release channel ryanodine receptor 1 (RyR1) in the sarcoplasmic reticulum (SR). Stac3 protein (SH3 and cysteine-rich domain 3) is an essential component of the EC coupling apparatus and a mutation in human STAC3 causes the debilitating Native Americanmyopathy (NAM), but the nature of how Stac3 acts on the DHPR and/or RyR1 is unknown. Using electron microscopy, electrophysiology, and dynamic imaging of zebrafish muscle fibers, we find significantly reduced DHPR levels, functionality, and stability in stac3 mutants. Furthermore, stac3(NAM) myofibers exhibited increased caffeine-induced Ca2+ release across a wide range of concentrations in the absence of altered caffeine sensitivity as well as increased Ca2+ in internal stores, which is consistent with increased SR luminal Ca2+. These findings define critical roles for Stac3 in EC coupling and human disease.