Zonisamide can ameliorate the voltage-dependence alteration of the T-type calcium channel Ca V 3.1 caused by a mutation
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RESEARCH
Zonisamide can ameliorate the voltage‑dependence alteration of the T‑type calcium channel C aV3.1 caused by a mutation responsible for spinocerebellar ataxia Naoyuki Hara1, Hiroyuki Morino2* , Yukiko Matsuda2, Kenichi Satoh3, Kouichi Hashimoto4, Hirofumi Maruyama1 and Hideshi Kawakami2
Abstract 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 C aV3.1 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 C aV3.1. 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 C aV3.1 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 C aV3.1. Keywords: Spinocerebellar ataxia, SCA42, CACNA1G, T-type calcium channel, CaV3.1, Tremor, Zonisamide Introduction A recurrent mutation of p.Arg1715His in CACNA1G, which encodes the low voltage-gated calcium channel CaV3.1 (T-type), alters the physiological properties of the channel and causes spinocerebellar ataxia 42 (SCA) *Correspondence: morino@hiroshima‑u.ac.jp 2 Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1‑2‑3 Kasumi, Minami‑ku, Hiroshima, Hiroshima 734‑8553, Japan Full list of author information is available at the end of the article
[1–5]. This mutation is located in the S4 voltage-sensor segment of C aV3.1. Patients with SCA42 present with a pure form of cerebellar ataxia, and some patients present with other symptoms such as dementia, truncal myoclonus, myokymia, and tremor [1–3]. We surveyed a family with SCA42, in which two patients presented with intractable resting
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