Clenbuterol-sensitive delayed outward potassium currents in a cell model of spinal and bulbar muscular atrophy.
Clenbuterol-sensitive delayed outward potassium currents in a cell model of spinal and bulbar muscular atrophy.
复制标题
脊髓和延髓肌萎缩细胞模型中克伦特罗敏感的延迟外向钾电流。
DOI：
10.1007/s00424-021-02559-6
复制
发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Musio,Carlo
中科院分区：
文献类型：
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作者：
Martínez-Rojas,VladimirA;Arosio,Daniele;Pennuto,Maria;Musio,Carlo
脊髓和延髓性肌萎缩症 (SBMA) 是一种由雄激素受体 (AR) 基因中的聚谷氨酰胺 (polyQ) 扩增引起的神经肌肉疾病。 SBMA 的特点是脑干和脊髓中运动神经元的选择性功能障碍和退化，其机制尚不清楚，离子通道调节可能在其他神经退行性疾病中发挥核心作用。据观察，β2-肾上腺素能激动剂克伦特罗可改善小鼠和患者来源的肌管的 SBMA 表型。然而，潜在的分子机制尚未阐明。在这里，我们揭示了运动神经元衍生的 MN-1 细胞中由 PolyQ 扩增的 AR 表达诱导的离子电流改变可通过给予克伦特罗而减弱。我们结合电生理学和药理学方法使我们能够揭示克伦特罗可以改变延迟的外向钾电流。总的来说，我们证明克伦特罗提供的保护通过调节 KV2 型外向钾电流恢复正常功能，可能有助于对 SBMA 运动神经元毒性的保护作用。
Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by polyglutamine (polyQ) expansions in the androgen receptor (AR) gene. SBMA is characterized by selective dysfunction and degeneration of motor neurons in the brainstem and spinal cord through still unclear mechanisms in which ion channel modulation might play a central role as for other neurodegenerative diseases. The beta2-adrenergic agonist clenbuterol was observed to ameliorate the SBMA phenotype in mice and patient-derived myotubes. However, the underlying molecular mechanism has yet to be clarified. Here, we unveil that ionic current alterations induced by the expression of polyQ-expanded AR in motor neuron-derived MN-1 cells are attenuated by the administration of clenbuterol. Our combined electrophysiological and pharmacological approach allowed us to reveal that clenbuterol modifies delayed outward potassium currents. Overall, we demonstrated that the protection provided by clenbuterol restores the normal function through the modulation of KV2-type outward potassium currents, possibly contributing to the protective effect on motor neuron toxicity in SBMA.