title: The arrestin-selective angiotensin AT1 receptor agonist [Sar1,Ile4,Ile8]-AngII negatively regulates bradykinin B2 receptor signaling via AT1-B2 receptor heterodimers.
abstract: The renin-angiotensin and kallikrein-kinin systems are key regulators of vascular tone and inflammation. Angiotensin II, the principal effector of the renin-angiotensin system, promotes vasoconstriction by activating angiotensin AT1 receptors. The opposing effects of the kallikrein-kinin system are mediated by bradykinin acting on B1 and B2 bradykinin receptors. The renin-angiotensin and kallikrein-kinin systems engage in cross-talk at multiple levels, including the formation of AT1-B2 receptor heterodimers. In primary vascular smooth muscle cells, we find that the arrestin pathway-selective AT1 agonist, [Sar(1),Ile(4),Ile(8)]-AngII, but not the neutral AT1 antagonist, losartan, inhibits endogenous B2 receptor signaling. In a transfected HEK293 cell model that recapitulates this effect, we find that the actions of [Sar(1),Ile(4), Ile(8)]-AngII require the AT1 receptor and result from arrestin-dependent co-internalization of AT1-B2 heterodimers. BRET50 measurements indicate that AT1 and B2 receptors efficiently heterodimerize. In cells expressing both receptors, pretreatment with [Sar(1),Ile(4),Ile(8)]-AngII blunts B2 receptor activation of Gq/11-dependent intracellular calcium influx and Gi/o-dependent inhibition of adenylyl cyclase. In contrast, [Sar(1),Ile(4),Ile(8)]-AngII has no effect on B2 receptor ligand affinity or bradykinin-induced arrestin3 recruitment. Both radioligand binding assays and quantitative microscopy-based analysis demonstrate that [Sar(1),Ile(4),Ile(8)]-AngII promotes internalization of AT1-B2 heterodimers. Thus, [Sar(1),Ile(4),Ile(8)]-AngII exerts lateral allosteric modulation of B2 receptor signaling by binding to the orthosteric ligand binding site of the AT1 receptor and promoting co-sequestration of AT1-B2 heterodimers. Given the opposing roles of the renin-angiotensin and kallikrein-kinin systems in vivo, the distinct properties of arrestin pathway-selective and neutral AT1 receptor ligands may translate into different pharmacologic actions.
authors: Department of Medicine, College of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors: Parker C
authors: PC
authors: Wilson
authors: Mi-Hye
authors: MH
authors: Lee
authors: Kathryn M
authors: KM
authors: Appleton
authors: Hesham M
authors: HM
authors: El-Shewy
authors: Thomas A
authors: TA
authors: Morinelli
authors: Yuri K
authors: YK
authors: Peterson
authors: Louis M
authors: LM
authors: Luttrell
authors: Ayad A
authors: AA
authors: Jaffa
mesh_terms: D000495:Allosteric Site; D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology; D019390:Arrestins / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006439:Hemodynamics; D006801:Humans; D007610:Kallikreins / Q000378:metabolism; D008024:Ligands; D019808:Losartan / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists* / Q000378:metabolism*; D043782:Receptor, Bradykinin B2 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D019390:Arrestins; D008024:Ligands; D044140:Receptor, Angiotensin, Type 1; D043782:Receptor, Bradykinin B2; C502020:angiotensin II, Sar(1)-Ile(4)-Ile(8)-; D000804:Angiotensin II; D007610:Kallikreins; D019204:GTP-Binding Proteins; D019808:Losartan; D002118:Calcium
keywords: Angiotensin; Arrestin; Biased Agonism; Bradykinin; G Protein-coupled Receptors (GPCR); G Proteins; Heterodimerization; Sequestration; Signal Transduction
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