SNF-6 is an acetylcholine transporter interacting with the dystrophin complex in Caenorhabditis elegans
SNF-6 is an acetylcholine transporter interacting with the dystrophin complex in Caenorhabditis elegans
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DOI：
10.1038/nature02798
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发表时间：
2004-08-19
期刊：
影响因子：
64.8
通讯作者：
McIntire, SL
中科院分区：
文献类型：
--
作者：
Kim, H;Rogers, MJ;McIntire, SL
肌营养不良症是最常见的人类遗传疾病之一，其特征是进行性肌肉退化。肌营养不良症是由肌营养不良蛋白-糖蛋白复合物 (DGC) 成分的遗传缺陷引起的，DGC 是一种存在于肌肉细胞质膜中的多聚体复合物 (1)。 DGC 将细胞内细胞骨架与细胞外基质连接起来，被认为对于维持肌肉的机械完整性 (2) 和组织信号分子 (3) 非常重要。然而，DGC 在疾病发病机制中的确切作用仍不确定(4)。秀丽隐杆线虫 DGC 基因突变会导致协调运动的特定缺陷，还可能导致肌肉退化(5-7)。在这里，我们表明，snf-6 基因的突变导致的表型与 DGC 突变体的表型无法区分，并且 snf-6 编码一种新型乙酰胆碱/胆碱转运蛋白。在突触活动增加期间，SNF-6 介导神经肌肉接头处乙酰胆碱的摄取。 SNF-6 还与 DGC 相互作用，DGC 基因的突变会导致神经肌肉接头处 SNF-6 的丢失。乙酰胆碱清除不当和肌肉长时间兴奋可能导致肌营养不良症的发病机制。
Muscular dystrophies are among the most common human genetic diseases and are characterized by progressive muscle degeneration. Muscular dystrophies result from genetic defects in components of the dystrophin-glycoprotein complex (DGC), a multimeric complex found in the muscle cell plasma membrane(1). The DGC links the intracellular cytoskeleton to the extracellular matrix and is thought to be important for maintaining the mechanical integrity of muscles(2) and organizing signalling molecules(3). The exact role of the DGC in the pathogenesis of disease has, however, remained uncertain(4). Mutations in Caenorhabditis elegans DGC genes lead to specific defects in coordinated movement and can also cause muscle degeneration(5-7). Here we show that mutations in the gene snf-6 result in phenotypes indistinguishable from those of the DGC mutants, and that snf-6 encodes a novel acetylcholine/choline transporter. SNF-6 mediates the uptake of acetylcholine at neuromuscular junctions during periods of increased synaptic activity. SNF-6 also interacts with the DGC, and mutations in DGC genes cause a loss of SNF-6 at neuromuscular junctions. Improper clearing of acetylcholine and prolonged excitation of muscles might contribute to the pathogenesis of muscular dystrophies.