Journal
CIRCULATION
Volume 128, Issue 15, Pages 1612-1622Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.113.002659
Keywords
genetic therapy; heart failure; hypertrophy; receptors; adrenergic; beta; signal transduction
Funding
- Italian ministry of University and Scientific Research, PRIN (Progetto di Ricerca di Interesse Nazionale)
- American Heart Association (Great Rivers Affiliate)
- National Institutes of Health [R01 HL085503, R37 HL061690, P01 HL075443, P01 HL108806, P01 HL091799, R01 HL091096]
- British Heart Foundation [PG/12/1/29276] Funding Source: researchfish
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Background The sphingosine-1-phosphate receptor 1 (S1PR1) and (1)-adrenergic receptor (1AR) 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 1ARs 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 1AR and S1PR1, we demonstrated that 1AR downregulation can occur after stimulation with sphingosine-1-phosphate (an S1PR1 agonist), whereas S1PR1 downregulation can be triggered by isoproterenol (a -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 -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 1AR overstimulation in heart failure.
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