β1-adrenoceptor Arg389Gly polymorphism confers differential β-arrestin-binding tropism in cardiac myocytes

Aim: The beta(1)-adrenergic receptor (AR) Arg389Gly polymorphism affects efficacy of its procontractile signaling in cardiomyocytes and carriers' responses to beta-blockers. To identify molecular mechanisms underlying functional differences between Arg389 and Gly389 beta(1)ARs, we examined their binding to beta-arrestins (beta arr-1 and -2), which mediate beta(1)AR signaling, in neonatal rat ventricular myocytes. Methods: We tested the beta(1)AR-beta arr interaction via beta(1)AR immunoprecipitation followed by beta arr immunoblotting. Results: beta arr1 binds both variants upon isoproterenol, carvedilol or metoprolol treatment in neonatal rat ventricular myocytes. Conversely, the potentially beneficial in the heart beta arr2 only interacts with the Arg389 receptor in response to isoproterenol or carvedilol. Conclusion: Arg389 confers unique beta arr2-interacting tropism to the beta(1)AR in cardiac myocytes, potentially underlying this variant's gain-of-function phenotype and better clinical responses to beta-blockers.