?1-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.

ABSTRACT: 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.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.We demonstrate that restoration of cardiac plasma membrane levels of S1PR1 produces beneficial effects that counterbalance the deleterious ?1AR overstimulation in heart failure.

SUBMITTER: Cannavo A 

PROVIDER: S-EPMC3952877 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature