内皮素-1 对人心房肌细胞 TRPC1 通道的调节。
Regulation of the TRPC1 channel by endothelin-1 in human atrial myocytes.
机构信息
Xiamen Cardiovascular Hospital, Medical School of Xiamen University, Xiamen, Fujian, China.
Xiamen Cardiovascular Hospital, Medical School of Xiamen University, Xiamen, Fujian, China.
出版信息
Heart Rhythm. 2019 Oct;16(10):1575-1583. doi: 10.1016/j.hrthm.2019.04.003. Epub 2019 Apr 4.
BACKGROUND
Our recent study demonstrated that the nonselective cation current mediated by the transient receptor potential canonical 1 (TRPC1) channel is activated by endothelin-1 (ET-1) in human atrial myocytes; however, the related signal molecules involved are unknown.
OBJECTIVE
The purpose of this study was to investigate how the TRPC1 channel is regulated by ET-1 and whether it is upregulated in human atria from patients with atrial fibrillation (AF).
METHODS
Whole-cell patch technique and molecular biology techniques were used in the study.
RESULTS
The ET-1-evoked TRPC1 current was inhibited by the ET-1 type A (ET) receptor antagonist BQ123 and the ET-1 type B (ET) receptor antagonist BQ788 as well as the protein kinase C inhibitor chelerythrine. ET receptor-mediated TRPC1 channel activity was selectively inhibited by the phosphoinositide-3-kinase inhibitor wortmannin, while ET receptor-mediated TRPC1 activity was inhibited by the phospholipase C inhibitor U73122. The messenger RNAs and proteins of the TRPC1 channel and ET receptor, but not the ET receptor, were significantly upregulated in atria from patients with AF. The basal TRPC1 current increased in AF myocytes, and the response to ET-1 was greater in AF myocytes than in sinus rhythm myocytes. ET-1 induced a delayed repolarization in 20% of AF myocytes.
CONCLUSION
These results demonstrate for the first time that TRPC1 activation by ET-1 is mediated by protein kinase C through the distinct phospholipids pathways phosphoinositide-3-kinase and phospholipase C and that the TRPC1 channel and ET receptor are upregulated in AF atria, which are likely involved in atrial electrical remodeling in patients with AF.
背景
我们最近的研究表明，瞬时受体电位经典型 1（TRPC1）通道介导的非选择性阳离子电流可被内皮素-1（ET-1）激活，但其涉及的相关信号分子尚不清楚。
目的
本研究旨在探讨 ET-1 如何调节 TRPC1 通道，以及其在心房颤动（AF）患者的人心房中是否上调。
方法
本研究采用全细胞膜片钳技术和分子生物学技术。
结果
ET-1 诱导的 TRPC1 电流被 ET-A 受体拮抗剂 BQ123 和 ET-B 受体拮抗剂 BQ788 以及蛋白激酶 C 抑制剂Chelerythrine 抑制。ET 受体介导的 TRPC1 通道活性被磷酸肌醇 3-激酶抑制剂wortmannin 选择性抑制，而 ET 受体介导的 TRPC1 活性被磷脂酶 C 抑制剂 U73122 抑制。TRPC1 通道和 ET 受体的信使 RNA 和蛋白，但不是 ET 受体，在 AF 患者的心房中明显上调。AF 心肌细胞中的基础 TRPC1 电流增加，ET-1 对 AF 心肌细胞的反应大于窦律心肌细胞。ET-1 可诱导 20%的 AF 心肌细胞产生延迟复极。
结论
这些结果首次表明，ET-1 通过蛋白激酶 C 通过独特的磷脂途径 PI3K 和 PLC 介导 TRPC1 的激活，并且在 AF 心房中 TRPC1 通道和 ET 受体上调，这可能参与了 AF 患者的心房电重构。
Zotero 插件