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β2-Adrenergic Receptor Redistribution in Heart Failure Changes cAMP Compartmentation

Science  26 Mar 2010:
Vol. 327, Issue 5973, pp. 1653-1657
DOI: 10.1126/science.1185988

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Heart Cell Signaling in 3D

A healthy heart relies on the proper transduction of cellular signals through the β1- and β2-adrenergic receptors (βARs), which are located on the surface of the heart's muscle cells (cardiomyocytes). The surface of these cells resembles a highly organized series of hills and valleys and it has been unclear whether this topography plays a role in the βAR signaling events that are critical to cell function. Nikolaev et al. (p. 1653, published online 25 February; see Perspective by Dorn) monitored the cyclic adenosine monophosphate (cAMP) signals generated by the βARs in living cardiomyocytes. In cells from healthy rats and from rats with heart failure, the β1ARs were localized across the entire cell surface. In contrast, the spatial localization of the β2ARs differed in healthy and failing cells. In healthy cardiomyocytes, the β2ARs resided exclusively within surface invaginations called transverse tubules, thereby producing spatially confined cAMP signals, whereas in failing cardiomyocytes, the β2ARs redistributed to other cell surface areas, thereby producing diffuse cAMP signals. Thus, changes in the spatial localization of β2AR-induced cAMP signaling may contribute to heart failure.

Abstract

The β1- and β2-adrenergic receptors (βARs) 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 βARs, 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 β2AR-induced cAMP signals are localized exclusively to the deep transverse tubules, whereas functional β1ARs are distributed across the entire cell surface. In cardiomyocytes derived from a rat model of chronic heart failure, β2ARs were redistributed from the transverse tubules to the cell crest, which led to diffuse receptor-mediated cAMP signaling. Thus, the redistribution of β2ARs in heart failure changes compartmentation of cAMP and might contribute to the failing myocardial phenotype.

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