Cell biological analysis of KATP channel in ischemic myocardium

缺血心肌KATP通道的细胞生物学分析

• 批准号: 13670707
• 负责人: OTANI Hideo
• 金额: $ 2.11万
• 依托单位: KYOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13670707/
• 关键词: KATP channel; KCNQ1; cell swelling; QT prolongation; myocardial ischemia; LQTs; SCN5A; KCNJ2; QT延長症候群; Andersen症候群; 不整脈; 虚血心筋保護; Kir6.1; SUR; CFTR; アンギオテンシンII

intracellular ATP level. Especially, in ischemic myocardium, K ATP channel is known to be one of the most important component, and several other channels which are modulated by intracellular ATP level. are also contributing by determining. action potential duration. We analyzed the function of these channel... by patch-clump method in cultured cells which overexpressing KCNQ1, the subunit of delayed rectifier K channel. Analyses using tyrosin kinase, ATP analogue, or phosphatidylinositol 4.5-bisghoshpate revealed that this channel protein has direct effects on cell swelling induced enhancement of slowly activating delayed rectifier K current. It is imortant to analyze the relationship between cell swelling in myocardial damage and KCNQ1 function In clinical medicine, acute myocardial infarction is frequently acompanies fatal dysrhythmias. QT prolongation, ECG change during exercise, and modulation by several drugs are most critical determinants of these dysrhythmias. Hereditary long QT syndrome is a nice model to analyze these factors. K channel anomalies (LQT1 and LQT2) are closely related with specific ECG changes during exercise, and has a possible profound significance to predict sudden death. We found a new mutation in SCN5A sodium channel protein, L1855A, and that induces sodium peak current reduction, and cusses lethal arrhythmia in bradycardia and drug challenge. We also discovered the mechanism how mutation at PIP binding site in KCNJ2 channel expressed dominant negative effect, and caused arrhythmia in patients with Anderson syndrome. To investigate how these disorders in ion channel affect ischemic myocardium causing dysrhythmia is one of the most challenging field

细胞内ATP水平。特别是，在缺血性心肌中，K ATP通道是最重要的组成部分之一，而其他几种通过细胞内ATP水平调节的通道。也通过确定做出贡献。动作潜在持续时间。我们通过培养的细胞中的贴片 - 束缚方法分析了这些通道的功能，这些细胞过表达KCNQ1，这是延迟整流器K通道的亚基。使用酪氨酸激酶，ATP类似物或磷脂酰肌醇4.5-二哥糖酸盐的分析表明，该通道蛋白对细胞肿胀诱导的诱导的延迟延迟整流k电流的增强具有直接影响。分析心肌损伤中的细胞肿胀与临床医学中KCNQ1功能之间的关系，急性心肌梗塞通常是致命的心律失常。 QT延长，运动过程中的ECG变化以及几种药物的调节是这些功能障碍的最关键决定因素。遗传长QT综合征是分析这些因素的一个不错的模型。 K通道异常（LQT1和LQT2）与运动过程中的特定ECG变化密切相关，并且可能具有预测猝死的深刻意义。我们在SCN5A钠通道蛋白L1855a中发现了一个新的突变，并诱导钠峰值电流减少，并在心动过缓和药物挑战中cusses致命的心律不齐。我们还发现了KCNJ2通道中PIP结合位点的突变如何表现出显性的负面影响，并导致Anderson综合征患者的心律不齐。研究这些疾病中的这些疾病如何影响缺血性心肌引起障碍性心律失常是最具挑战性的领域之一

项目成果

Kubota T: "Evidence for a single nucleotide polymorphism in the KCNQ1 potassium channel that underlies susceptibility to life-threatening arrhythmias"J Cardiovasc Electrophysiol. 12(11). 1223-1229 (2001)

Kubota T：“KCNQ1 钾通道中的单核苷酸多态性是危及生命的心律失常易感性的证据”J Cardiovasc Electrophysiol。

Kubota T, Horie M, Otani H, et al.: "Evidence for a single nucleotide polymorphism in the KCNQ1 potassium channel that underlies susceptibility to life-threatening arrhythmias"J Cardiovasc Electrophysiol. 12(11). 1223-1229 (2001)

Kubota T、Horie M、Otani H 等人：“KCNQ1 钾通道中单核苷酸多态性的证据是危及生命的心律失常的易感性”J Cardiovasc Electrophysiol。

Yoshida H.: "Bradycardia-induced long QT syndrome caused by a de novo missense mutation in the S2-S3 inner loop of HERG"Am J Med Genet.2001 Feb 1. 98(4). 348-352 (2001)

Yoshida H.：“HERG S2-S3 内环中的从头错义突变导致心动过缓诱发的长 QT 综合征”Am J Med Genet.2001 Feb 1. 98(4)。

Haruna T: "Alpha1-adrenoceptor-mediated breakdown of phosphatidylinositol 4,5-bisphosphate inhibits pinacidil-activated"Circ Res. 91(3). 232-239 (2002)

Haruna T：“α1-肾上腺素受体介导的磷脂酰肌醇 4,5-二磷酸分解抑制吡那地尔激活”Circ Res。

Makita N.: "Drug-induced long-QT syndrome associated with a subclinical SCN5A mutation"Circulation. 2002 Sep 3. 106(10). 1269-1274 (2002)

Makita N.：“与亚临床 SCN5A 突变相关的药物诱导的长 QT 综合征”循环。