The dystrophin complex controls bk channel localization and muscle activity in Caenorhabditis elegans.
The dystrophin complex controls bk channel localization and muscle activity in Caenorhabditis elegans.
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DOI：
10.1371/journal.pgen.1000780
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发表时间：
2009-12
期刊：
影响因子：
4.5
通讯作者：
McIntire SL
中科院分区：
文献类型：
--
作者：
Kim H;Pierce-Shimomura JT;Oh HJ;Johnson BE;Goodman MB;McIntire SL
肌营养不良蛋白相关蛋白复合物 (DAPC) 的遗传缺陷导致多种病理状况，包括肌营养不良、心肌病和血管痉挛。从人类到秀丽隐杆线虫的保守 DAPC 成分表明具有相似的分子功能。线虫 DAPC 突变体表现出由于长时间的肌肉兴奋和收缩而导致的独特的运动缺陷。在这里，我们表明，线虫 DAPC 对于 SLO-1 的正确定位至关重要，SLO-1 是大电导、电压和钙依赖性钾 (BK) 通道，在正常生理条件下在肌肉中传导主要的外向整流电流。通过分析与 DAPC 突变体具有相同表型的突变体，我们鉴定了新的 islo-1 基因，该基因编码具有两个预测的跨膜结构域的蛋白质。我们证明 ISLO-1 作为一种新型接头分子，将 DAPC 与肌肉中的 SLO-1 连接起来。我们发现 DAPC 或 ISLO-1 的缺陷会破坏肌肉中 SLO-1 的正常定位。与 SLO-1 需要高钙浓度才能完全激活的观察结果一致，我们发现 SLO-1 位于肌肉中的 L 型钙通道附近，从而提供了一种将钙内流与外向整流电流耦合的机制。我们的结果表明，DAPC 通过将 SLO-1 通道定位于秀丽隐杆线虫肌肉富含钙的区域来调节肌肉兴奋性。肌营养不良蛋白是一种长棒状蛋白质，与肌肉中的几种膜蛋白和细胞质蛋白形成复合物。这种肌营养不良蛋白复合物成分的遗传缺陷导致多种形式的肌营养不良症，包括杜氏肌营养不良症。秀丽隐杆线虫拥有肌营养不良蛋白复合物，其成分的突变会导致肌肉缺陷，表明肌营养不良蛋白复合物在肌肉中具有进化保守的作用。哺乳动物中越来越多的证据表明，营养不良的肌肉表现出异常的钙稳态。然而，尚不清楚抗肌营养不良蛋白复合物的缺陷如何与钙稳态相关。在一项秀丽隐杆线虫遗传学研究中，我们发现一种新型接头蛋白将肌营养不良蛋白复合物与介导肌肉失活的钙敏感钾通道连接起来。我们进一步证明，肌营养不良蛋白复合物和衔接蛋白都将钾通道定位在靠近肌肉激活钙通道的位置。这种安排确保伴随肌肉激活的钙增加与肌肉失活相结合。肌营养不良蛋白复合物或接头的缺陷会破坏钾通道的定位，从而导致肌肉激活时间延长和钙离子增加。我们的研究提供了肌营养不良蛋白复合物调节细胞信号传导和肌肉兴奋性的机制。
Genetic defects in the dystrophin-associated protein complex (DAPC) are responsible for a variety of pathological conditions including muscular dystrophy, cardiomyopathy, and vasospasm. Conserved DAPC components from humans to Caenorhabditis elegans suggest a similar molecular function. C. elegans DAPC mutants exhibit a unique locomotory deficit resulting from prolonged muscle excitation and contraction. Here we show that the C. elegans DAPC is essential for proper localization of SLO-1, the large conductance, voltage-, and calcium-dependent potassium (BK) channel, which conducts a major outward rectifying current in muscle under the normal physiological condition. Through analysis of mutants with the same phenotype as the DAPC mutants, we identified the novel islo-1 gene that encodes a protein with two predicted transmembrane domains. We demonstrate that ISLO-1 acts as a novel adapter molecule that links the DAPC to SLO-1 in muscle. We show that a defect in either the DAPC or ISLO-1 disrupts normal SLO-1 localization in muscle. Consistent with observations that SLO-1 requires a high calcium concentration for full activation, we find that SLO-1 is localized near L-type calcium channels in muscle, thereby providing a mechanism coupling calcium influx with the outward rectifying current. Our results indicate that the DAPC modulates muscle excitability by localizing the SLO-1 channel to calcium-rich regions of C. elegans muscle. Dystrophin is a long rod-shaped protein that forms a complex with several membrane and cytoplasmic proteins in muscle. Genetic defects in components of this dystrophin complex are responsible for many forms of muscular dystrophy, including Duchenne muscular dystrophy. C. elegans possesses the dystrophin complex and mutations in its components cause muscular defects, indicating that the dystrophin complex has an evolutionary conserved role in muscle. Accumulating evidence in mammals indicates that dystrophic muscle exhibits an abnormal calcium homeostasis. It is not clear how defects in the dystrophin complex are linked to calcium homeostasis, however. In a C. elegans genetic study we found that a novel adaptor protein links the dystrophin complex to a calcium-sensitive potassium channel that mediates muscle inactivation. We further demonstrated that both the dystrophin complex and the adaptor protein localize the potassium channel in a close proximity to a muscle-activating calcium channel. This arrangement ensures that calcium increases accompanied by muscle activation are coupled to muscle inactivation. Defects in the dystrophin complex or the adaptor disrupt the localization of the potassium channel, thereby resulting in prolonged muscle activation and calcium ion increases. Our study provides a mechanism by which the dystrophin complex regulates cellular signaling and muscle excitability.
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