An activator of voltage-gated K+ channels Kv1.1 as a therapeutic candidate for episodic ataxia type 1

Ilenio Servettini, Giuseppe Talani, Alfredo Megaro, Maria Dolores Setzu, Francesca Biggio, Michelle Briffa, Luca Guglielmi, Nicoletta Savalli, Francesca Binda, Francis Delicata, Gilles Bru-Mercier, Neville Vassallo, Vittorio Maglione, Ruben J. Cauchi, Alba Di Pardo, Maria Collu, Paola Imbrici, Luigi Catacuzzeno, Maria Cristina D’Adamo, Riccardo OlceseMauro Pessia

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Loss-of-function mutations in the KCNA1(Kv1.1) gene cause episodic ataxia type 1 (EA1), a neurological disease characterized by cerebellar dysfunction, ataxic attacks, persistent myokymia with painful cramps in skeletal muscles, and epilepsy. Precision medicine for EA1 treatment is currently unfeasible, as no drug that can enhance the activity of Kv1.1-containing channels and offset the functional defects caused by KCNA1 mutations has been clinically approved. Here, we uncovered that niflumic acid (NFA), a currently prescribed analgesic and anti-inflammatory drug with an excellent safety profile in the clinic, potentiates the activity of Kv1.1 channels. NFA increased Kv1.1 current amplitudes by enhancing the channel open probability, causing a hyperpolarizing shift in the voltage dependence of both channel opening and gating charge movement, slowing the OFF-gating current decay. NFA exerted similar actions on both homomeric Kv1.2 and heteromeric Kv1.1/Kv1.2 channels, which are formed in most brain structures. We show that through its potentiating action, NFA mitigated the EA1 mutation–induced functional defects in Kv1.1 and restored cerebellar synaptic transmission, Purkinje cell availability, and precision of firing. In addition, NFA ameliorated the motor performance of a knock-in mouse model of EA1 and restored the neuromuscular transmission and climbing ability in Shaker (Kv1.1) mutant Drosophila melanogaster flies (Sh5). By virtue of its multiple actions, NFA has strong potential as an efficacious single-molecule-based therapeutic agent for EA1 and serves as a valuable model for drug discovery.

Original languageEnglish
Article numbere2207978120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number31
DOIs
Publication statusPublished - Aug 1 2023

Keywords

  • Kv1.1(KCNA1)
  • Kv1.2(KCNA2)
  • OMIM160120
  • episodic ataxia type 1
  • niflumic acid

ASJC Scopus subject areas

  • General

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