微管介导的β2AR转化和功能在失败的心脏中的调节
Zoe Kwan1,2, Binoy Paulose Nadappuram2,3, Manton M Leung4
1National Heart and Lung Institute (Z.K., S.M., A.L., K.S.A., J.C., I.K., J.F., J.L.S.-A., C.A.M., P.S., B.W.-S., P.T.W., J.G.), Imperial College London, United Kingdom.
Circulation research
|October 23, 2023
概括
微管体依赖性贩运指导β-1和β-2上腺体受体 (β-AR) mRNA在心肌细胞中的定位. 心力衰竭改变了这种局部化,影响了受体功能和循环腺单酸盐信号传递.
科学领域:
- 心血管生物学 心血管生物学
- 细胞生物学 细胞生物学
- 分子心脏病学分子心脏病学
背景情况:
- 贝塔-1上腺素受体 (β1AR) 和贝塔-2上腺素受体 (β2AR) 信号传输极大地影响心脏功能和心力衰竭.
- 控制心脏β-ARs空间分布和功能细分的机制尚未完全理解.
- 局部翻译和微管体依赖的mRNA贩运是心肌细胞中蛋白质细分的新兴调节者.
研究的目的:
- 调查假设β-AR mRNA贩运和局部翻译决定了它们在心肌细胞中的细分.
- 阐明微管在调节β-AR mRNA局部化和功能中的作用.
- 检查心力衰竭的背景下β-AR mRNA局部化是如何改变的.
主要方法:
- 单个分子光 in situ 杂交和亚细胞纳米活检以映射大鼠心肌细胞中的β-AR mRNA定位.
- 维布拉斯治疗破坏微管,并评估对β-AR定位和功能的影响.
- 免疫光和高通量福斯特共振能量转移显微镜,以评估受体局部化和相互作用.
- mRNA-蛋白共同检测试验以确定β-AR转化部位.
- 对心肌梗塞后心肌细胞和心肌细胞的分析,以研究心力衰竭中的β-AR mRNA再分配.
主要成果:
- β1AR和β2ARmRNA表现出不同的局部化模式:β1AR是周核的,而β2AR是分散分布的.
- 微管中断将β2AR转录转移到周核区域,并减少功能性膜受体.
- β2AR转录在与翻译蛋白非常接近的地方被发现,这表明本地化翻译.
- 在心脏衰竭中,由于横管体重塑,β1AR和β2ARmRNA都会重新分布到细胞外围.
- 这种重新分配与心力衰竭中的β2AR功能受损有关.
结论:
- 微管体依赖性贩运不对称地控制健康心肌细胞中的β1AR和β2ARmRNA定位.
- 这种贩运决定了β-ARs在等离子体膜上的明显分离.
- 在心力衰竭中,横管改造会改变β-AR mRNA的局部化,导致扭曲的β2AR介导信号传输.
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