β3-Adrenoceptor redistribution impairs NO/cGMP/PDE2 signalling in failing cardiomyocytes
- Imperial College London, United Kingdom
- University of Würzburg, Germany
- Université Catholique de Louvain, Belgium
- Universitätsklinikum Hamburg Eppendorf, Germany
Abstract
Cardiomyocyte b3-adrenoceptors (b3-ARs) coupled to soluble guanylyl cyclase (sGC)-dependent production of the second messenger 3',5'-cyclic guanosine monophosphate (cGMP) have been shown to protect from heart failure. However, the exact localization of these receptors to fine membrane structures and subcellular compartmentation of b3-AR/cGMP signals underpinning this protection in health and disease remain elusive. Here, we used a Förster Resonance Energy Transfer (FRET)-based cGMP biosensor combined with scanning ion conductance microscopy (SICM) to show that functional β3-ARs are mostly confined to the T-tubules of healthy rat cardiomyocytes. Heart failure, induced via myocardial infarction, causes a decrease of the cGMP levels generated by these receptors and a change of subcellular cGMP compartmentation. Furthermore, attenuated cGMP signals led to impaired phosphodiesterase 2 dependent negative cGMP-to-cAMP cross-talk. In conclusion, topographic and functional reorganization of the b3-AR/cGMP signalosome happens in heart failure and should be considered when designing new therapies acting via this receptor.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files are provided for all figures to eLife journal.
Article and author information
Author details
Sophie Schobesberger
Funding
British Heart Foundation (12/18/30088)
- Julia Gorelik
Wellcome (WT090594)
- Julia Gorelik
Deutsche Forschungsgemeinschaft (Fr 1725/3-2)
- Andreas Friebe
- Viacheslav O Nikolaev
National Institutes of Health (ROI-HL grant 126802)
- Julia Gorelik
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All procedures performed in the UK were carried out according to the standards for the care and use of animal subjects determined by the UK Home Office (ASPA1986 Amendments Regulations 2012) incorporating the EU directive 2010/63/EU. The Animal Welfare and Ethical Review Body Committee of Imperial College London approved all protocols.The parts of the investigation, which were performed in Germany, conformed to the guide for the care and use of laboratory animals published by the National Institutes of Health (Bethesda, Maryland; Publication No. 85-23, revised 2011, published by National Research Council, Washington, D.C.). The experimental procedures were in accordance with the German Law for the Protection of Animals and with the guidelines of the European Community.
Copyright
© 2020, Schobesberger et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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β3-Adrenoceptor redistribution impairs NO/cGMP/PDE2 signalling in failing cardiomyocytes
eLife 9:e52221.
https://doi.org/10.7554/eLife.52221
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