| Project/Area Number |
22K20906
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund |
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| Review Section |
0902:General internal medicine and related fields
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| Research Institution | National Cardiovascular Center Research Institute |
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Principal Investigator |
Byambajav Tserenlkham 国立研究開発法人国立循環器病研究センター, オープンイノベーションセンター, リサーチフェロー (60963527)
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| Project Period (FY) |
2022-08-31 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | KCND3 / potassium channel / gain of function change / quinidine / SSRIs / Kv4.3 variants / electrophysiology / gain-of-function / neurological disorders / early repolarization / epilepsy / Kv4.3 / patch-clamp method / sudden cardiac death / arrhythmia / refractory epilepsy |
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| Outline of Research at the Start |
KCND3 variants were identified in patients, and the pathogenicity of these variants have not been elucidated. We have already constructed the plasmid with these KCND3 variants. Using cultured cells transfected with KCND3 variants, I try to elucidate the electrophysiological mechanism of early repolarization (RE) by patch-clamp method, and the analysis will be beneficial for the elucidation of the pathogenesis of SUDEP. Next, I search for effective therapeutic agents for pediatric patients with RE.
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| Outline of Final Research Achievements |
De novo and heterozygous KCND3 variants, p.V401L and p.V401M were identified in two young patients with refractory epilepsy. In the electrophysiological analysis, Chinese Hamster Ovary (CHO) cells expressing variant channels showed significant increase of current densities compared to those with WT. The activation curves of Ito with variants significantly shifted to leftward. In addition, significant slow inactivation time constants were observed. Related to the slow inactivation of variants, the recovery from inactivation in variants channels was significantly slow. We next conducted pharmacological investigation and examined the inhibitory effect of quinidine and Selective Serotonin Reuptake Inhibitors (SSRIs). Micromolar concentration of quinidine and SSRIs normalized the slow inactivation of variant channels in a concentration-dependent manner.
The variant carrying patients might have risk of sudden cardiac death in epilepsy, and quinidine and SSRIs can be therapeutic options.
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| Academic Significance and Societal Importance of the Research Achievements |
De novo and heterozygous KCND3 variants, p.V401L and p.V401M were identified and the gain-of-functional changes of these Ito channels by a KCND3 variants were reversed by quinidine and SSRIs. Therefore, these candidates can be therapeutic options to prevent sudden cardiac death in epilepsy.
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