Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK.
Science. 2010 Mar 26;327(5973):1653-7. doi: 10.1126/science.1185988. Epub 2010 Feb 25.
The beta1- and beta2-adrenergic receptors (betaARs) 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 betaARs, 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 beta2AR-induced cAMP signals are localized exclusively to the deep transverse tubules, whereas functional beta1ARs are distributed across the entire cell surface. In cardiomyocytes derived from a rat model of chronic heart failure, beta2ARs 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.
心肌细胞表面的β1-和β2-肾上腺素能受体（βAR）通过调节第二信使环磷酸腺苷（cAMP）的产生，对心脏功能和心力衰竭的发展产生不同的影响。这些与异三聚体鸟苷酸结合蛋白（G 蛋白）偶联的βAR 在心肌细胞中的空间定位及其定位的功能意义尚不清楚。我们结合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，在来自健康成年大鼠和小鼠的心肌细胞中，空间受限的β2AR 诱导的 cAMP 信号仅局限于深横管，而功能性β1AR 则分布在整个细胞表面。在慢性心力衰竭大鼠模型来源的心肌细胞中，β2AR 从横管重新分布到细胞嵴，导致弥散的受体介导的 cAMP 信号。因此，心力衰竭中β2AR 的重新分布改变了 cAMP 的区室化，可能导致衰竭心肌表型。
