title: 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.
authors.affiliation: Department of Physiology, Faculty of Medicine, Semmelweis University, P. O. Box 2, H-1428 Budapest, Hungary.
authors.forename: András D
authors.initials: AD
authors.lastname: Tóth
authors.affiliation: Department of Physiology, Faculty of Medicine, Semmelweis University, P. O. Box 2, H-1428 Budapest, Hungary; MTA-SE Laboratory of Molecular Physiology, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
authors.forename: Pál
authors.initials: P
authors.lastname: Gyombolai
authors.affiliation: Department of Physiology, Faculty of Medicine, Semmelweis University, P. O. Box 2, H-1428 Budapest, Hungary; MTA-SE Laboratory of Molecular Physiology, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
authors.forename: Bence
authors.initials: B
authors.lastname: Szalai
authors.affiliation: Department of Physiology, Faculty of Medicine, Semmelweis University, P. O. Box 2, H-1428 Budapest, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Várnai
authors.affiliation: Department of Physiology, Faculty of Medicine, Semmelweis University, P. O. Box 2, H-1428 Budapest, Hungary; MTA-SE Laboratory of Molecular Physiology, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Turu
authors.affiliation: Department of Physiology, Faculty of Medicine, Semmelweis University, P. O. Box 2, H-1428 Budapest, Hungary; MTA-SE Laboratory of Molecular Physiology, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary. Electronic address: Hunyady@eok.sote.hu.
authors.forename: László
authors.initials: L
authors.lastname: Hunyady
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D016466:CHO Cells; D019556:COS Cells; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002522:Chlorocebus aethiops; D003412:Cricetulus; D019281:Dimerization; D019204:GTP-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D009842:Oligopeptides / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists / Q000378:metabolism*; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology; D000071557:beta-Arrestins / Q000378:metabolism*
chemical_list: D001562:Benzimidazoles; D001713:Biphenyl Compounds; D009842:Oligopeptides; D044140:Receptor, Angiotensin, Type 1; D018343:Receptors, Adrenergic, beta-2; D013777:Tetrazoles; D000071557:beta-Arrestins; C555535:sarcosine-arginyl-valyl-tyrosyl-lysyl-histidyl-prolyl-alanine; D000804:Angiotensin II; D019204:GTP-Binding Proteins; C081643:candesartan
keywords: Arrestin; BRET; Biased signaling; GPCR; Heterodimerization