离子通道的配对生物合成稳定了刺激性,并减轻了心律失常
Margaret B Jameson1, Erick B Ríos-Pérez1, Fang Liu1
1Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705.
概括
协调的离子通道mRNA配对确保了心脏电稳定性. 与SCN5A和KCNH2等相关蛋白质的转录的这种共同翻译关联通过共同调节通道功能来缓解心律失常.
科学领域:
- 分子和细胞生物学分子和细胞生物学
- 心血管生理学心血管生理学
- 生物物理学的生物物理.
背景情况:
- 协调的离子通道表达对心脏功能和心律至关重要.
- 离子通道的失调会导致心律失常.
- 以前的研究表明,mRNA与心脏NaV1.5 (SCN5A) 和hERG1 (KCNH2) 有关,但功能意义尚不清楚.
研究的目的:
- 综合调查多个离子通道转录 (KCNH2,SCN5A,CACNA1C,KCNQ1) 与相应的新生蛋白质的共净化.
- 阐明蛋白质合成过程中离子通道mRNA关联的机制和功能影响.
- 要确定这种mRNA关联是否影响心脏电稳定性和心律失常.
主要方法:
- 单分子光在位杂交 (smFISH) 与免疫光相结合,可视化mRNA-蛋白质同位化.
- 普罗米辛治疗,以评估翻译在mRNA关联中的作用.
- 通过shRNA介导的KCNH2的耗尽,以评估对关联的mRNA和通道电流的共同敲击效应.
- 多电极阵列 (MEA) 记录以评估药物或基因操纵下的心律.
主要成果:
- 发现多个离子通道转录 (KCNH2,SCN5A,CACNA1C,KCNQ1) 与它们各自的新生的通道蛋白共同净化.
- 道蛋白质由离散的mRNA合成为异型对,其关联取决于完整的翻译机制或新生蛋白质的存在.
- 一个转录 (KCNH2) 的耗尽导致相关转录和编码通道电流的同时减少,这种现象在功能相关的转录中观察到.
- 与选择性通道抑制相比,Co-Knockdown减轻了前节律失常行为,这表明它具有保护作用.
结论:
- 功能相关的离子通道mRNA以协调,共翻译的方式结合在一起.
- 这种mRNA关联依赖于翻译机械和新生的蛋白质,形成宏分子复合体.
- 通过共同翻译的mRNA协会对补充性离子通道的共同调节赋予了电稳定性并减轻了前节律失常的风险.
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