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<p>Voltage-gated potassium channels, Kv3.1, Kv3.2, Kv3.3, and Kv3.4, facilitate rapid repolarization and shape action potentials, which are crucial to maintaining high-frequency firing. Little is known about the expression and function of Kv3 channels in skeletal muscle. We show that these channels are expressed in type IIa/IIx fibers, and their transcript levels progressively increase from postnatal age to adulthood in physiological context. In mature myofibers, the Kv3.1 and Kv3.4 channels are enriched in the muscle triads. The expression of the Kv3 channel is lost upon acute motor unit damage, in mouse models of amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA), and the skeletal muscle of patients with sporadic ALS. Early treatment of ALS and SBMA mice with AUT00201, a positive allosteric modulator of Kv3 channels, improved the phenotype of ALS mice specifically, suggesting that positive modulation of Kv3 channels is a novel therapeutic option for patients with ALS.</p>

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Kv3 channel agonist ameliorates the phenotype of a mouse model of amyotrophic lateral sclerosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月14日

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  • Manuela Marabita,
  • Caterina Marchioretti,
  • Aishwarya Aravamudhan,
  • Simona Zito,
  • Antonella Falconieri,
  • Emanuela Zuccaro,
  • Roberta Andreotti,
  • Lisa Gambarotto,
  • Samuele Metti,
  • Marika Tonellato,
  • Valentina Adami,
  • Kyung Ho Park,
  • Martin J. Gunthorpe,
  • Charles H. Large,
  • Agostino Marasco,
  • Sara Vianello,
  • Jessica Rosati,
  • Elisa Belluzzi,
  • Assunta Pozzuoli,
  • Carlo Biz,
  • Pietro Ruggieri,
  • Manuela Basso,
  • Angelo Poletti,
  • Giuseppe Alvaro,
  • Gianni Sorarù,
  • Paolo Bonaldo,
  • Ornella Rossetto,
  • Nadia Pilati,
  • Maria Pennuto

摘要

Voltage-gated potassium channels, Kv3.1, Kv3.2, Kv3.3, and Kv3.4, facilitate rapid repolarization and shape action potentials, which are crucial to maintaining high-frequency firing. Little is known about the expression and function of Kv3 channels in skeletal muscle. We show that these channels are expressed in type IIa/IIx fibers, and their transcript levels progressively increase from postnatal age to adulthood in physiological context. In mature myofibers, the Kv3.1 and Kv3.4 channels are enriched in the muscle triads. The expression of the Kv3 channel is lost upon acute motor unit damage, in mouse models of amyotrophic lateral sclerosis (ALS) and spinal and bulbar muscular atrophy (SBMA), and the skeletal muscle of patients with sporadic ALS. Early treatment of ALS and SBMA mice with AUT00201, a positive allosteric modulator of Kv3 channels, improved the phenotype of ALS mice specifically, suggesting that positive modulation of Kv3 channels is a novel therapeutic option for patients with ALS.