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Zonisamide can ameliorate the voltage-dependence alteration of the T-type calcium channel CaV3.1 caused by a mutation responsible for spinocerebellar ataxia.
Hara, Naoyuki; Morino, Hiroyuki; Matsuda, Yukiko; Satoh, Kenichi; Hashimoto, Kouichi; Maruyama, Hirofumi; Kawakami, Hideshi.
Afiliación
  • Hara N; Department of Clinical Neuroscience and Therapeutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, 734-8551, Japan.
  • Morino H; Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, 734-8553, Japan. morino@hiroshima-u.ac.jp.
  • Matsuda Y; Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, 734-8553, Japan.
  • Satoh K; The Center for Data Science Education and Research, Shiga University, 1-1-1 Banba, Hikone, Shiga, 522-8522, Japan.
  • Hashimoto K; Department of Neurophysiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, 734-8551, Japan.
  • Maruyama H; Department of Clinical Neuroscience and Therapeutics, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, 734-8551, Japan.
  • Kawakami H; Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, 734-8553, Japan.
Mol Brain ; 13(1): 163, 2020 11 26.
Article en En | MEDLINE | ID: mdl-33243296
Spinocerebellar ataxia (SCA) 42 is caused by a mutation in CACNA1G, which encodes the low voltage-gated calcium channel CaV3.1 (T-type). Patients with SCA42 exhibit a pure form of cerebellar ataxia. We encountered a patient with the p.Arg1715His mutation, suffering from intractable resting tremor, particularly head tremor. This symptom improved with the administration of low-dose of zonisamide (ZNS), a T-type calcium channel blocker effective for treating Parkinson's disease and epilepsy. Previous electrophysiological studies showed that the voltage dependence of this mutant CaV3.1 was shifted toward the positive potential. This abnormal shift was considered a factor related to disease onset and symptoms. In this study, we performed whole-cell recordings of GFP-expressing HEK293T cells that expressed wild-type or mutant CaV3.1 and investigated the changes in the abnormal shift of voltage dependence of the mutant CaV3.1. The results showed that ZNS in an amount equivalent to the patient's internal dose significantly ameliorated the abnormal shift in the mutant CaV3.1, giving values close to those in the wild-type. On the other hand, ZNS did not affect the voltage dependence of wild-type CaV3.1. Because CaV3.1 is known to be involved in tremogenesis, modulation of the voltage dependence of mutant CaV3.1 by ZNS might have contributed to improvement in the intractable tremor of our patient with SCA42. Moreover, efonidipine, another T-type calcium channel blocker, had no effect on tremors in our patient with SCA42 and did not improve the abnormal shift in the voltage dependence of the mutant CaV3.1. This indicates that ZNS is distinct from other T-type calcium channel blockers in terms of modulation of the voltage dependence of the mutant CaV3.1.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ataxias Espinocerebelosas / Canales de Calcio Tipo T / Zonisamida / Mutación Límite: Humans Idioma: En Revista: Mol Brain Asunto de la revista: BIOLOGIA MOLECULAR / CEREBRO Año: 2020 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Reino Unido

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ataxias Espinocerebelosas / Canales de Calcio Tipo T / Zonisamida / Mutación Límite: Humans Idioma: En Revista: Mol Brain Asunto de la revista: BIOLOGIA MOLECULAR / CEREBRO Año: 2020 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Reino Unido