β3-Adrenoceptor redistribution impairs NO/cGMP/PDE2 signalling in failing cardiomyocytes.

Sophie Schobesberger, Peter T Wright, Claire Poulet, Jose L Sanchez Alonso Mardones, Catherine Mansfield, Andreas Friebe, Sian E Harding, Jean-Luc Balligand, Viacheslav O Nikolaev, Julia Gorelik

eLife 2020 Mar 31

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Cardiomyocyte β3-adrenoceptors (β3-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 β3-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 two dependent negative cGMP-to-cAMP cross-talk. In conclusion, topographic and functional reorganization of the β3-AR/cGMP signalosome happens in heart failure and should be considered when designing new therapies acting via this receptor. © 2020, Schobesberger et al.

Citation

Sophie Schobesberger, Peter T Wright, Claire Poulet, Jose L Sanchez Alonso Mardones, Catherine Mansfield, Andreas Friebe, Sian E Harding, Jean-Luc Balligand, Viacheslav O Nikolaev, Julia Gorelik. β3-Adrenoceptor redistribution impairs NO/cGMP/PDE2 signalling in failing cardiomyocytes. eLife. 2020 Mar 31;9