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Potential benefit of channel activators in loss-of-function primary potassium channelopathies causing heredoataxia

Abstract: Abstract Potassium channels (KCN) are transmembrane complexes that regulate the resting membrane potential and the duration of action potentials in cells. The opening of KCN brings about an efux of K+ ions that induces cell repolarization after depo larization, returns the transmembrane potential to its resting state, and enables for continuous spiking ability. The aim of this work was to assess the role of KCN dysfunction in the pathogenesis of hereditary ataxias and the mechanisms of action of KCN opening agents (KCO). In consequence, a review of the ad hoc medical literature was performed. Among hereditary KCN diseases causing ataxia, mutated Kv3.3, Kv4.3, and Kv1.1 channels provoke spinocerebellar ataxia (SCA) type 13, SCA19/22, and episodic ataxia type 1 (EA1), respectively. The K+ efux was found to be reduced in experimental models of these diseases, resulting in abnormally prolonged depolarization and incomplete repolarization, thereby interfering with repetitive discharges in the cells. Hence, substances able to promote normal spiking activity in the cerebellum could provide symptomatic beneft. Although drugs used in clinical practice do not activate Kv3.3 or Kv4.3 directly, available KCO prob ably could ameliorate ataxic symptoms in SCA13 and SCA19/22, as verifed with acetazolamide in EA1, and retigabine in a mouse model of hypokalemic periodic paralysis. To summarize, ataxia could possibly be improved by non-specifc KCO in SCA13 and SCA19/22. The identifcation of new specifc KCO agents will undoubtedly constitute a promising therapeutic strategy for these diseases.

Otras publicaciones de la misma revista o congreso con autores/as de la Universidad de Cantabria

 Fuente: The Cerebellum, 2023

Editorial: Springer

 Año de publicación: 2023

Nº de páginas: 5

Tipo de publicación: Artículo de Revista

 DOI: 10.1007/s12311-023-01584-8

ISSN: 1473-4230,1473-4222

Url de la publicación: https://doi.org/10.1007/s12311-023-01584-8