The neuroprotective drug riluzole acts via small conductance Ca2+-activated K+ channels to ameliorate defects in spinal muscular atrophy models.
The neuroprotective drug riluzole acts via small conductance Ca2+-activated K+ channels to ameliorate defects in spinal muscular atrophy models.
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DOI：
10.1523/jneurosci.1536-12.2013
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发表时间：
2013-04-10
期刊：
影响因子：
--
通讯作者：
Hart AC
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文献类型：
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作者：
Dimitriadi M;Kye MJ;Kalloo G;Yersak JM;Sahin M;Hart AC
脊髓性肌萎缩症（SMA）是一种隐性神经肌肉疾病，是由运动神经元生存蛋白（SMN）功能减弱引起的。为了确定SMA相关的细胞过程，在果蝇和C. elegans SMA模型来鉴定SMN功能表型丧失的修饰剂。一类这样的遗传修饰剂是小电导，Ca2+激活的K+（SK）通道。当细胞内钙增加时，SK通道允许钾离子流出，并且可以被神经保护药物利鲁唑激活。后者是唯一一种已被证明在治疗肌萎缩性侧索硬化症（ALS）方面有效的药物，尽管效果不明显。目前尚不清楚利鲁唑是否可以延长SMA患者的寿命或改善症状，因为以前的研究有限，并且不足以得出任何结论。利鲁唑在运动神经元疾病中的关键生化靶点尚不清楚，但利鲁唑的药理学靶点包括SK通道。我们在这里研究利鲁唑在两种不同的SMA模型中的影响。在脊椎动物神经元中，利鲁唑治疗恢复了由SMN减少引起的轴突生长。此外，利鲁唑改善了C。elegans SMA模型和SK通道功能是这种有益效果所必需的。我们认为利鲁唑通过作用于SK通道改善运动神经元功能，并认为SK通道可能是SMA患者的重要治疗靶点。
Spinal muscular atrophy (SMA), a recessive neuromuscular disorder, is caused by diminished function of the Survival Motor Neuron (SMN) protein. To define the cellular processes pertinent to SMA, parallel genetic screens were undertaken in Drosophila and C. elegans SMA models to identify modifiers of the SMN loss of function phenotypes. One class of such genetic modifiers was the small conductance, Ca2+-activated K+ (SK) channels. SK channels allow efflux of potassium ions when intracellular calcium increases and can be activated by the neuroprotective drug riluzole. The latter is the only drug with proven, albeit modest, efficacy in the treatment of Amyotrophic Lateral Sclerosis (ALS). It is unclear if riluzole can extend lifespan or ameliorate symptoms in SMA patients as previous studies were limited and of insufficient power to draw any conclusions. The critical biochemical target of riluzole in motorneuron disease is not known, but the pharmacological targets of riluzole include SK channels. We examine here the impact of riluzole in two different SMA models. In vertebrate neurons, riluzole treatment restored axon outgrowth caused by diminished SMN. Additionally, riluzole ameliorated the neuromuscular defects in a C. elegans SMA model and SK channel function was required for this beneficial effect. We propose that riluzole improves motorneuron function by acting on SK channels and suggest that SK channels may be important therapeutic targets for SMA patients.