Institute of Biophysics (IBF), Trento Unit, National Research Council (CNR) & LabSSAH, Bruno Kessler Foundation (FBK), Trento, Italy.
Department of Biomedical Sciences (DSB), University of Padova, Padova, Italy.
Pflugers Arch. 2021 Aug;473(8):1213-1227. doi: 10.1007/s00424-021-02559-6. Epub 2021 May 22.
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 K2-type outward potassium currents, possibly contributing to the protective effect on motor neuron toxicity in SBMA.
脊髓延髓肌肉萎缩症（SBMA）是一种由雄激素受体（AR）基因中的多聚谷氨酰胺（polyQ）扩展引起的神经肌肉疾病。SBMA 的特征是通过仍然不清楚的机制，选择性地使脑干和脊髓中的运动神经元功能障碍和退化，其中离子通道调节可能像其他神经退行性疾病一样发挥核心作用。β2-肾上腺素能激动剂克仑特罗被观察到可改善小鼠和患者来源的肌管中的 SBMA 表型。然而，其潜在的分子机制尚未阐明。在这里，我们揭示了在运动神经元衍生的 MN-1 细胞中表达多聚 Q 扩展的 AR 引起的离子电流改变，可被克仑特罗减弱。我们的联合电生理和药理学方法使我们能够揭示克仑特罗修饰延迟外向钾电流。总的来说，我们证明了克仑特罗通过调节 K2 型外向钾电流提供的保护作用恢复了正常功能，这可能有助于 SBMA 中对运动神经元毒性的保护作用。
