Chang Di, Tong Wu, Kai Gao, Na Li, Huifang Song, Lili Wang, Haojie Sun, Jingyun Yi, Xinran Zhang, Jiexin Chen, Mala Shah, Yuwu Jiang, Zhuo Huang
{"title":"卡维地洛可抑制癫痫相关 KCNT1 基因突变导致的神经元过度兴奋。","authors":"Chang Di, Tong Wu, Kai Gao, Na Li, Huifang Song, Lili Wang, Haojie Sun, Jingyun Yi, Xinran Zhang, Jiexin Chen, Mala Shah, Yuwu Jiang, Zhuo Huang","doi":"10.1111/bph.17360","DOIUrl":null,"url":null,"abstract":"<p><strong>Background and purpose: </strong>KCNT1 encodes a sodium-activated potassium channel (Slack channel), and its mutation can cause several forms of epilepsy. Traditional antiepileptic medications have limited efficacy in treating patients with KCNT1 mutations. Here, we describe one heterozygous KCNT1 mutation, M267T, in a patient with EIMFS. The pathological channel properties of this mutation and its effect on neuronal excitability were investigated. Additionally, this study aimed to develop a medication for effective prevention of KCNT1 mutation-induced seizures.</p><p><strong>Experimental approach: </strong>Wild-type or mutant KCNT1 plasmids were expressed heterologously in Xenopus laevis oocytes, and channel property assessment and drug screening were performed based on two-electrode voltage-clamp recordings. The single-channel properties were investigated using the excised inside-out patches from HEK293T cells. Through in utero electroporation, WT and M267T Slack channels were expressed in the hippocampal CA1 pyramidal neurons in male mice, followed by the examination of the electrical properties using the whole-cell current-clamp technique. The kainic acid-induced epilepsy model in male mice was used to evalute the antiseizure effects of carvedilol.</p><p><strong>Key results: </strong>The KCNT1 M267T mutation enhanced Slack channel function by increasing single-channel open probability. Through screening 16 FDA-approved ion channel blockers, we found that carvedilol effectively reversed the mutation-induced gain-of-function channel properties. Notably, the KCNT1 M267T mutation in the mouse hippocampal CA1 pyramidal neurons affected afterhyperpolarization properties and induced neuronal hyperexcitability, which was inhibited by carvedilol. Additionally, carvedilol exhibited antiseizure effects in the kainic acid-induced epilepsy model.</p><p><strong>Conclusion and implication: </strong>Our findings suggest carvedilol as a new potential candidate for treatment of epilepsies.</p>","PeriodicalId":9262,"journal":{"name":"British Journal of Pharmacology","volume":" ","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2024-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Carvedilol inhibits neuronal hyperexcitability caused by epilepsy-associated KCNT1 mutations.\",\"authors\":\"Chang Di, Tong Wu, Kai Gao, Na Li, Huifang Song, Lili Wang, Haojie Sun, Jingyun Yi, Xinran Zhang, Jiexin Chen, Mala Shah, Yuwu Jiang, Zhuo Huang\",\"doi\":\"10.1111/bph.17360\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background and purpose: </strong>KCNT1 encodes a sodium-activated potassium channel (Slack channel), and its mutation can cause several forms of epilepsy. Traditional antiepileptic medications have limited efficacy in treating patients with KCNT1 mutations. Here, we describe one heterozygous KCNT1 mutation, M267T, in a patient with EIMFS. The pathological channel properties of this mutation and its effect on neuronal excitability were investigated. Additionally, this study aimed to develop a medication for effective prevention of KCNT1 mutation-induced seizures.</p><p><strong>Experimental approach: </strong>Wild-type or mutant KCNT1 plasmids were expressed heterologously in Xenopus laevis oocytes, and channel property assessment and drug screening were performed based on two-electrode voltage-clamp recordings. The single-channel properties were investigated using the excised inside-out patches from HEK293T cells. 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Carvedilol inhibits neuronal hyperexcitability caused by epilepsy-associated KCNT1 mutations.
Background and purpose: KCNT1 encodes a sodium-activated potassium channel (Slack channel), and its mutation can cause several forms of epilepsy. Traditional antiepileptic medications have limited efficacy in treating patients with KCNT1 mutations. Here, we describe one heterozygous KCNT1 mutation, M267T, in a patient with EIMFS. The pathological channel properties of this mutation and its effect on neuronal excitability were investigated. Additionally, this study aimed to develop a medication for effective prevention of KCNT1 mutation-induced seizures.
Experimental approach: Wild-type or mutant KCNT1 plasmids were expressed heterologously in Xenopus laevis oocytes, and channel property assessment and drug screening were performed based on two-electrode voltage-clamp recordings. The single-channel properties were investigated using the excised inside-out patches from HEK293T cells. Through in utero electroporation, WT and M267T Slack channels were expressed in the hippocampal CA1 pyramidal neurons in male mice, followed by the examination of the electrical properties using the whole-cell current-clamp technique. The kainic acid-induced epilepsy model in male mice was used to evalute the antiseizure effects of carvedilol.
Key results: The KCNT1 M267T mutation enhanced Slack channel function by increasing single-channel open probability. Through screening 16 FDA-approved ion channel blockers, we found that carvedilol effectively reversed the mutation-induced gain-of-function channel properties. Notably, the KCNT1 M267T mutation in the mouse hippocampal CA1 pyramidal neurons affected afterhyperpolarization properties and induced neuronal hyperexcitability, which was inhibited by carvedilol. Additionally, carvedilol exhibited antiseizure effects in the kainic acid-induced epilepsy model.
Conclusion and implication: Our findings suggest carvedilol as a new potential candidate for treatment of epilepsies.
期刊介绍:
The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries.
Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues.
In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.