An Alpha-Catulin Homologue Controls Neuromuscular Function through Localization of the Dystrophin Complex and BK Channels in Caenorhabditis elegans
An Alpha-Catulin Homologue Controls Neuromuscular Function through Localization of the Dystrophin Complex and BK Channels in Caenorhabditis elegans
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DOI：
10.1371/journal.pgen.1001077
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发表时间：
2010-08-01
期刊：
影响因子：
4.5
通讯作者：
Kim, Hongkyun
中科院分区：
文献类型：
--
作者：
Abraham, Linu S.;Oh, Hyun J.;Kim, Hongkyun
大电导、电压和钙依赖性钾 (BK) 通道是钙介导的生理过程的主要负反馈调节器，并与肌肉功能障碍和神经系统疾病有关。除了膜去极化之外，BK 通道的激活还需要胞质钙的增加。因此，BK 通道靠近钙通道的定位对其功能至关重要。在旨在分离秀丽隐杆线虫 BK 通道新调节因子 SLO-1 的遗传筛选中，我们鉴定了 ctn-1，它编码与细胞骨架蛋白 a-catenin 和 vinculin 同源的 α-catulin 同源物。 ctn-1 突变体类似于 slo-1 功能丧失突变体，以及肌营养不良蛋白复合物受损的突变体。我们确定 CTN-1 使用两种不同的机制将 SLO-1 定位在肌肉和神经元中。在肌肉中，CTN-1 利用肌营养不良蛋白复合物将 SLO-1 通道定位在 L 型钙通道附近。在神经元中，CTN-1 参与将 SLO-1 定位到独立于肌营养不良蛋白复合物的特定域。我们的结果表明，CTN-1 确保了 SLO-1 在钙纳米结构域内的定位，从而在肌肉和神经元中发挥着至关重要的作用。
The large conductance, voltage- and calcium-dependent potassium (BK) channel serves as a major negative feedback regulator of calcium-mediated physiological processes and has been implicated in muscle dysfunction and neurological disorders. In addition to membrane depolarization, activation of the BK channel requires a rise in cytosolic calcium. Localization of the BK channel near calcium channels is therefore critical for its function. In a genetic screen designed to isolate novel regulators of the Caenorhabditis elegans BK channel, SLO-1, we identified ctn-1, which encodes an alpha-catulin homologue with homology to the cytoskeletal proteins a-catenin and vinculin. ctn-1 mutants resemble slo-1 loss-of-function mutants, as well as mutants with a compromised dystrophin complex. We determined that CTN-1 uses two distinct mechanisms to localize SLO-1 in muscles and neurons. In muscles, CTN-1 utilizes the dystrophin complex to localize SLO-1 channels near L-type calcium channels. In neurons, CTN-1 is involved in localizing SLO-1 to a specific domain independent of the dystrophin complex. Our results demonstrate that CTN-1 ensures the localization of SLO-1 within calcium nanodomains, thereby playing a crucial role in muscles and neurons.