Angiotensin type 1A receptor regulates β-arrestin binding of the β2-adrenergic receptor via heterodimerization

Abstract

Heterodimerization between angiotensin type 1A receptor (AT₁R) and β₂-adrenergic receptor (β₂AR) 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 β₂AR is affected by activation of AT₁Rs. Costimulation with angiotensin II and isoproterenol markedly enhanced the interaction between β₂AR and β-arrestins, by prolonging the lifespan of β₂AR-induced β-arrestin2 clusters at the plasma membrane. While candesartan, a conventional AT₁R antagonist, had no effect on the β-arrestin2 binding to β₂AR, TRV120023, a β-arrestin biased agonist, enhanced the interaction. These findings reveal a new crosstalk mechanism between AT₁R and β₂AR, and suggest that enhanced β-arrestin2 binding to β₂AR can contribute to the pharmacological effects of biased AT₁R agonists.

Keywords: Arrestin; BRET; Biased signaling; GPCR; Heterodimerization.