Submit Data |  Help |  Video Tutorials |  News |  Publications |  FTP Download |  REST API |  Citing RGD |  Contact   

ß1-adrenergic receptor and sphingosine-1-phosphate receptor 1 (S1PR1) reciprocal downregulation influences cardiac hypertrophic response and progression to heart failure: protective role of S1PR1 cardiac gene therapy.

Authors: Cannavo, Alessandro  Rengo, Giuseppe  Liccardo, Daniela  Pagano, Gennaro  Zincarelli, Carmela  De Angelis, Maria Carmen  Puglia, Roberto  Di Pietro, Elisa  Rabinowitz, Joseph E  Barone, Maria Vittoria  Cirillo, Plinio  Trimarco, Bruno  Palmer, Timothy M  Ferrara, Nicola  Koch, Walter J  Leosco, Dario  Rapacciuolo, Antonio 
Citation: Cannavo A, etal., Circulation. 2013 Oct 8;128(15):1612-22. doi: 10.1161/CIRCULATIONAHA.113.002659. Epub 2013 Aug 22.
Pubmed: (View Article at PubMed) PMID:23969695
DOI: Full-text: DOI:10.1161/CIRCULATIONAHA.113.002659

BACKGROUND: The sphingosine-1-phosphate receptor 1 (S1PR1) and ß1-adrenergic receptor (ß1AR) are G-protein-coupled receptors expressed in the heart. These 2 receptors have opposing actions on adenylyl cyclase because of differential G-protein coupling. Importantly, both of these receptors can be regulated by the actions of G-protein-coupled receptor kinase-2, which triggers desensitization and downregulation processes. Although classic signaling paradigms suggest that simultaneous activation of ß1ARs and S1PR1s in a myocyte would simply result in opposing action on cAMP production, in this report we have uncovered a direct interaction between these 2 receptors, with regulatory involvement of G-protein-coupled receptor kinase-2.
METHODS AND RESULTS: In HEK (human embryonic kidney) 293 cells overexpressing both ß1AR and S1PR1, we demonstrated that ß1AR downregulation can occur after stimulation with sphingosine-1-phosphate (an S1PR1 agonist), whereas S1PR1 downregulation can be triggered by isoproterenol (a ß-adrenergic receptor agonist) treatment. This cross talk between these 2 distinct G-protein-coupled receptors appears to have physiological significance, because they interact and show reciprocal regulation in mouse hearts undergoing chronic ß-adrenergic receptor stimulation and in a rat model of postischemic heart failure.
CONCLUSIONS: We demonstrate that restoration of cardiac plasma membrane levels of S1PR1 produces beneficial effects that counterbalance the deleterious ß1AR overstimulation in heart failure.


Disease Annotations
Objects Annotated

Additional Information

CRRD Object Information
CRRD ID: 13792712
Created: 2018-09-21
Species: All species
Last Modified: 2018-09-21
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.