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Science 327 (5973): 1653-1657

Copyright © 2010 by the American Association for the Advancement of Science

β2-Adrenergic Receptor Redistribution in Heart Failure Changes cAMP Compartmentation

Viacheslav O. Nikolaev,1,2 Alexey Moshkov,1 Alexander R. Lyon,1 Michele Miragoli,1 Pavel Novak,1,3 Helen Paur,1 Martin J. Lohse,2 Yuri E. Korchev,3 Sian E. Harding,1 Julia Gorelik1,*

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.

1 Department of Cardiac Medicine, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK.
2 Institute of Pharmacology and Toxicology and Rudolf-Virchow-Center, University of Würzburg, Versbacher Strasse 9, Würzburg 97078, Germany.
3 Division of Medicine, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK.

* To whom correspondence should be addressed. E-mail: j.gorelik{at}imperial.ac.uk

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