Epac2调解了心脏β1-上腺素依赖的质晶状网Ca2+泄漏和心律失常
Laëtitia Pereira1, Hongqiang Cheng, Dieu Hung Lao
1Department of Pharmacology, University of California Davis, Davis, CA 95616-8636, USA.
Circulation
|February 1, 2013
概括
β-上腺素受体 (β-AR) 的激活会通过Epac2和CaMKIIδ触发心律失常,导致肉质细胞网膜Ca2+) 泄漏. 这一途径涉及RyR2-S2814酸化,有助于心脏功能障碍.
科学领域:
- 心血管生理学心血管生理学
- 分子心脏病学分子心脏病学
- 信号传输 信号传输
背景情况:
- β-上腺素受体 (β-AR) 激活通过cAMP影响心脏功能,激活蛋白激酶A和Epac.
- 对于PKA和Epac在调解心脏Ca2+信号传递和心律失常方面的β-AR影响的相互作用尚不清楚.
- 选择性Epac激活可以诱导质网膜 (SR) Ca2+释放,涉及CaMKII和氨酸受体 (RyR) 酸化.
研究的目的:
- 为了调查β-AR激活是否会诱导Epac介导的SR Ca2+) 泄漏和心律失常.
- 确定Epac1,Epac2,β(1) -AR,β(2) -AR和CaMKIIδ在这个过程中的作用.
- 检查RyR2-S2814酸化对β-AR诱导的心脏事件的贡献.
主要方法:
- 使用淘汰赛小鼠进行Epac1,Epac2或两者兼用.
- 使用特定的Epac激活剂 (8-CPT) 和β-AR激动剂.
- 采用了蛋白激酶A抑制,β(1) -AR/β(2) -AR阻断,以及CaMKII抑制 (KN93).
- 评估SR Ca2+) 泄漏,心律失常,心脏功能和RyR2-S2814酸化.
主要成果:
- 由8-CPT引起的SR Ca(2+) 泄漏在Epac2-KO和双KO小鼠中被消除,但不是Epac1-KO小鼠.
- 与野生类型相比,在Epac2-KO小鼠中,β-AR诱导的心律失常发生的频率较低.
- 当PKA被抑制时,β(1) -AR激活,但不是β(2) -AR,模仿了Epac激活器对SR Ca(2+) 泄漏的作用.
- 抑制CaMKII和对CaMKIIδ或RyR2-S2814酸化的基因切除防止了8-CPT诱导的SR Ca2+) 泄漏.
结论:
- β(1) -AR激活利用Epac2通过CaMKIIδ依赖的RyR2-S2814酸化诱导SR Ca(2+) 泄漏.
- 这种Epac2-CaMKIIδ-RyR2通路是导致β-AR诱导的心律失常的重要因素.
- 确定的途径将β-AR刺激与通过改变的Ca2+) 处理将心脏功能降低联系在一起.
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