β<sub>3</sub>-Adrenoceptor redistribution impairs NO/cGMP/PDE2 signalling in failing cardiomyocytes.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 32228862.
- Also identified by DOI 10.7554/eLife.52221 and PMC identifier 7138611.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Cardiomyocyte β<sub>3</sub>-adrenoceptors (β<sub>3</sub>-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 β<sub>3</sub>-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 β<sub>3</sub>-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 β<sub>3</sub>-AR/cGMP signalosome happens in heart failure and should be considered when designing new therapies acting via this receptor.
Medical subject headings
- Cyclic GMP
- Cyclic Nucleotide Phosphodiesterases, Type 2
- Myocytes, Cardiac
- Receptors, Adrenergic, beta-3
- Signal Transduction