2021 Fiscal Year Final Research Report
Pharmacological analysis of selective KACh channel blocker for gene mutations responsible for hereditary bradyarrhythmia
Project/Area Number |
20K16132
|
Research Category |
Grant-in-Aid for Early-Career Scientists
|
Allocation Type | Multi-year Fund |
Review Section |
Basic Section 48030:Pharmacology-related
|
Research Institution | Osaka University |
Principal Investigator |
YAMADA Noriaki 大阪大学, 国際共創大学院学位プログラム推進機構, 特任助教(常勤) (40850144)
|
Project Period (FY) |
2020-04-01 – 2022-03-31
|
Keywords | イオンチャネル / 遺伝性不整脈 / 遺伝子変異 / カリウムチャネル阻害薬 / ゲノム解析 |
Outline of Final Research Achievements |
The acetylcholine-activated potassium channel (KACh channel) expressed in the heart is a heterotetramer of two potassium channel subunits, encoded by the KCNJ3 and KCNJ5 genes. The KACh channel contributes to parasympathetic control of heart rate. Mutations in these channel genes or genes involved in the channel activation are reported to be causative for hereditary bradyarrhythmias. The activity of these mutants seemed to be associated with the pathophysiology of the disease. The aims of this study were to characterize channel properties of various mutations and to evaluate their sensitivity to a selective KACh channel blocker. Pharmacological analysis of this compound for various mutations was performed in cellular electrophysiological studies. This compound was found to have an inhibitory effect not only on wild type but on mutant channels, suggesting that it may be an effective novel therapeutic agent for bradyarrhythmia patients harboring a mutation in the KACh related genes.
|
Free Research Field |
薬理学
|
Academic Significance and Societal Importance of the Research Achievements |
選択的KAChチャネル阻害薬が、変異によりチャネル電流が異常増加することで徐脈性不整脈を発症するというその病因が明確であるイオンチャネル病に対して、病態機序に基づいた新規の分子特異的治療薬となり得ることを示した。 これまで遺伝性徐脈の原因分子を標的とした治療薬はなく、一般の徐脈性不整脈に対する治療と同様、心臓ペースメーカー治療に頼らざるを得ないのが現状である。既存の不整脈病名と診断されたものの遺伝子解析が行われていないKAChチャネル病の患者が国内外で潜在的に存在すると予想され、ペースメーカー植え込み手術の代替となる新たな治療法になり得る可能性があり、今後の研究開発につなげていく必要がある。
|