β2-Adrenergic Receptor Redistribution in Heart Failure Changes cAMP Compartmentation
β2-Adrenergic Receptor Redistribution in Heart Failure Changes cAMP Compartmentation
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DOI：
10.1126/science.1185988
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发表时间：
2010-03-26
期刊：
影响因子：
56.9
通讯作者：
Gorelik, Julia
中科院分区：
文献类型：
--
作者：
Nikolaev, Viacheslav O.;Moshkov, Alexey;Gorelik, Julia
心肌细胞表面的β（1）-和β（2）-肾上腺素能受体（β AR）通过调节第二信使环磷酸腺苷（cAMP）的产生来介导对心脏功能和心力衰竭发展的不同作用。在心肌细胞中的空间定位的这些bAR，这是偶联到异源三聚体鸟嘌呤核苷酸结合蛋白（G蛋白），其定位的功能意义一直不清楚。我们结合了纳米级活细胞扫描离子电导和荧光共振能量转移显微镜技术，发现在健康成年大鼠和小鼠的心肌细胞中，空间受限的β（2）AR诱导的cAMP信号仅定位于深横小管，而功能性β（1）AR分布在整个细胞表面。在来自慢性心力衰竭大鼠模型的心肌细胞中，β 2 AR从横小管重新分布到细胞嵴，导致弥漫性受体介导的cAMP信号传导。因此，心力衰竭时β 2 AR的重新分布改变了cAMP的区室化，并可能导致心力衰竭的心肌表型。
The beta(1)- and beta(2)-adrenergic receptors (beta ARs) on the surface of cardiomyocytes mediate distinct effects on cardiac function and the development of heart failure by regulating production of the second messenger cyclic adenosine monophosphate (cAMP). The spatial localization in cardiomyocytes of these bARs, which are coupled to heterotrimeric guanine nucleotide-binding proteins (G proteins), and the functional implications of their localization have been unclear. We combined nanoscale live-cell scanning ion conductance and fluorescence resonance energy transfer microscopy techniques and found that, in cardiomyocytes from healthy adult rats and mice, spatially confined beta(2)AR-induced cAMP signals are localized exclusively to the deep transverse tubules, whereas functional beta(1)ARs are distributed across the entire cell surface. In cardiomyocytes derived from a rat model of chronic heart failure, beta(2)ARs were redistributed from the transverse tubules to the cell crest, which led to diffuse receptor-mediated cAMP signaling. Thus, the redistribution of beta(2)ARs in heart failure changes compartmentation of cAMP and might contribute to the failing myocardial phenotype.