β1-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

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.