Angiotensin type 1A receptor regulates β-arrestin binding of the β 2 -adrenergic receptor via heterodimerization.

Heterodimerization between angiotensin type 1A receptor (AT1 R) and β2 -adrenergic receptor (β2 AR) has been shown to modulate G protein-mediated effects of these receptors. Activation of G protein-coupled receptors (GPCRs) leads to β-arrestin binding, desensitization, internalization and G protein-independent signaling of GPCRs. Our aim was to study the effect of heterodimerization on β-arrestin coupling. We found that β-arrestin binding of β2 AR is affected by activation of AT1 Rs. Costimulation with angiotensin II and isoproterenol markedly enhanced the interaction between β2 AR and β-arrestins, by prolonging the lifespan of β2 AR-induced β-arrestin2 clusters at the plasma membrane. While candesartan, a conventional AT1 R antagonist, had no effect on the β-arrestin2 binding to β2 AR, TRV120023, a β-arrestin biased agonist, enhanced the interaction. These findings reveal a new crosstalk mechanism between AT1 R and β2 AR, and suggest that enhanced β-arrestin2 binding to β2 AR can contribute to the pharmacological effects of biased AT1 R agonists.