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The arrestin-selective angiotensin AT1 receptor agonist [Sar1,Ile4,Ile8]-AngII negatively regulates bradykinin B2 receptor signaling via AT1-B2 receptor heterodimers

Show simple item record Wilson P.C. Lee M.-H. Appleton K.M. El-Shewy H.M. Morinelli T.A. Peterson Y.K. Luttrell L.M. Jaffa A.A.
dc.contributor.editor Jun-2013 2017-10-05T15:30:57Z 2017-10-05T15:30:57Z 2013
dc.identifier 10.1074/jbc.M113.472381
dc.identifier.issn 00219258
dc.description.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,Ile4,Ile8]-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 [Sar1,Ile4, Ile8]-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,Ile4,Ile8]-AngII blunts B2 receptor activation of Gq-11-dependent intracellular calcium influx and Gi-o-dependent inhibition of adenylyl cyclase. In contrast, [Sar1,Ile 4,Ile8]-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,Ile4,Ile8]-AngII promotes internalization of AT1-B2 heterodimers. Thus, [Sar1,Ile4,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.
dc.format.extent Pages: (18872-18884)
dc.language English
dc.publisher BETHESDA
dc.relation.ispartof Publication Name: Journal of Biological Chemistry; Publication Year: 2013; Volume: 288; no. 26; Pages: (18872-18884);
dc.source Scopus
dc.title The arrestin-selective angiotensin AT1 receptor agonist [Sar1,Ile4,Ile8]-AngII negatively regulates bradykinin B2 receptor signaling via AT1-B2 receptor heterodimers
dc.type Article
dc.contributor.affiliation Wilson, P.C., Department of Medicine, College of Medicine, Medical University of South Carolina, Charleston, SC 29425, United States
dc.contributor.affiliation Lee, M.-H., Department of Medicine, College of Medicine, Medical University of South Carolina, Charleston, SC 29425, United States
dc.contributor.affiliation Appleton, K.M., Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, SC 29425, United States
dc.contributor.affiliation El-Shewy, H.M., Department of Medicine, College of Medicine, Medical University of South Carolina, Charleston, SC 29425, United States
dc.contributor.affiliation Morinelli, T.A., Department of Medicine, College of Medicine, Medical University of South Carolina, Charleston, SC 29425, United States
dc.contributor.affiliation Peterson, Y.K., Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, SC 29425, United States
dc.contributor.affiliation Luttrell, L.M., Department of Medicine, College of Medicine, Medical University of South Carolina, Charleston, SC 29425, United States, Department of Biochemistry and Molecular Biology, College of Medicine, Medical University of South Carolina, Charleston, SC 29425, United States, Research Service of the Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401, United States
dc.contributor.affiliation Jaffa, A.A., Department of Medicine, College of Medicine, Medical University of South Carolina, Charleston, SC 29425, United States, Departments of Biochemistry and Molecular Genetics, American University of Beirut, Beirut 1107-2020, Lebanon
dc.contributor.authorAddress Luttrell, L.M.; Division of Endocrinology, Diabetes and Medical Genetics, Dept. of Medicine, Medical University of South Carolina, 96 Jonathan Lucas St., Charleston, SC 29425, United States; email:
dc.contributor.authorCorporate University: American University of Beirut Medical Center; Faculty: Faculty of Medicine; Department: Biochemistry and Molecular Genetics;
dc.contributor.authorDepartment Biochemistry and Molecular Genetics
dc.contributor.faculty Faculty of Medicine
dc.contributor.authorInitials Wilson, PC
dc.contributor.authorInitials Lee, MH
dc.contributor.authorInitials Appleton, KM
dc.contributor.authorInitials El-Shewy, HM
dc.contributor.authorInitials Morinelli, TA
dc.contributor.authorInitials Peterson, YK
dc.contributor.authorInitials Luttrell, LM
dc.contributor.authorInitials Jaffa, AA
dc.contributor.authorReprintAddress Luttrell, LM (reprint author), Med Univ S Carolina, Dept Med, Div Endocrinol Diabet and Med Genet, 96 Jonathan Lucas St,Suite 816CSB,MSC624, Charleston, SC 29425 USA.
dc.contributor.authorUniversity American University of Beirut Medical Center
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dc.description.citedCount 6
dc.description.citedTotWOSCount 7
dc.description.citedWOSCount 7
dc.format.extentCount 13
dc.identifier.coden JBCHA
dc.identifier.pubmedID 23661707
dc.identifier.scopusID 84879563066
dc.publisher.address 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA
dc.relation.ispartofFundingAgency R01 HL087986, NIH, National Institutes of Health
dc.relation.ispartofFundingAgency HL077192, NIH, National Institutes of Health
dc.relation.ispartofFundingAgency R01 DK55524, NIH, National Institutes of Health
dc.relation.ispartofFundingAgency F30 DK083208, NIH, National Institutes of Health
dc.relation.ispartofFundingAgency S10 RR027777, NCRR, National Center for Research Resources
dc.relation.ispartOfISOAbbr J. Biol. Chem.
dc.relation.ispartOfIssue 26
dc.relation.ispartofPubTitle Journal of Biological Chemistry
dc.relation.ispartofPubTitleAbbr J. Biol. Chem.
dc.relation.ispartOfVolume 288
dc.source.ID WOS:000321335800025
dc.type.publication Journal
dc.subject.otherChemCAS adenylate cyclase, 9012-42-4
dc.subject.otherChemCAS angiotensin, 1407-47-2
dc.subject.otherChemCAS bradykinin, 58-82-2, 5979-11-3
dc.subject.otherChemCAS calcium, 14092-94-5, 7440-70-2
dc.subject.otherChemCAS kallikrein, 8006-48-2, 9001-01-8
dc.subject.otherChemCAS losartan, 114798-26-4
dc.subject.otherChemCAS renin, 61506-93-2, 9015-94-5
dc.subject.otherChemCAS retina S antigen, 113315-03-0
dc.subject.otherChemCAS Angiotensin II, 11128-99-7
dc.subject.otherChemCAS Arrestins
dc.subject.otherChemCAS Calcium, 7440-70-2
dc.subject.otherChemCAS GTP-Binding Proteins, 3.6.1.-
dc.subject.otherChemCAS Kallikreins, 3.4.21.-
dc.subject.otherChemCAS Ligands
dc.subject.otherChemCAS Losartan, 114798-26-4
dc.subject.otherChemCAS Receptor, Angiotensin, Type 1
dc.subject.otherChemCAS Receptor, Bradykinin B2
dc.subject.otherChemCAS angiotensin II, (Sar1,Ile4,Ile8)-
dc.subject.otherIndex Allosteric modulation
dc.subject.otherIndex Intracellular calcium
dc.subject.otherIndex Ligand-binding sites
dc.subject.otherIndex Radioligand binding
dc.subject.otherIndex Receptor activation
dc.subject.otherIndex Receptor signaling
dc.subject.otherIndex Renin-angiotensin system
dc.subject.otherIndex Vascular Smooth Muscle Cells
dc.subject.otherIndex Biological membranes
dc.subject.otherIndex Chemical activation
dc.subject.otherIndex Ligands
dc.subject.otherIndex adenylate cyclase
dc.subject.otherIndex angiotensin
dc.subject.otherIndex angiotensin 1 receptor
dc.subject.otherIndex angiotensin II [1 sarcosine 4 isoleucine 8 isoleucine]
dc.subject.otherIndex angiotensin II derivative
dc.subject.otherIndex arrestin 3
dc.subject.otherIndex bradykinin
dc.subject.otherIndex bradykinin B2 receptor
dc.subject.otherIndex calcium
dc.subject.otherIndex heterodimer
dc.subject.otherIndex kallikrein
dc.subject.otherIndex kinin
dc.subject.otherIndex losartan
dc.subject.otherIndex renin
dc.subject.otherIndex retina S antigen
dc.subject.otherIndex unclassified drug
dc.subject.otherIndex allosterism
dc.subject.otherIndex animal cell
dc.subject.otherIndex animal experiment
dc.subject.otherIndex animal model
dc.subject.otherIndex article
dc.subject.otherIndex binding site
dc.subject.otherIndex calcium cell level
dc.subject.otherIndex calcium transport
dc.subject.otherIndex cell strain HEK293
dc.subject.otherIndex controlled study
dc.subject.otherIndex drug mechanism
dc.subject.otherIndex enzyme inhibition
dc.subject.otherIndex genetic transfection
dc.subject.otherIndex human
dc.subject.otherIndex human cell
dc.subject.otherIndex internalization
dc.subject.otherIndex ligand binding
dc.subject.otherIndex negative feedback
dc.subject.otherIndex nonhuman
dc.subject.otherIndex priority journal
dc.subject.otherIndex protein expression
dc.subject.otherIndex protein transport
dc.subject.otherIndex rat
dc.subject.otherIndex receptor affinity
dc.subject.otherIndex receptor binding
dc.subject.otherIndex receptor blocking
dc.subject.otherIndex signal transduction
dc.subject.otherIndex smooth muscle fiber
dc.subject.otherIndex vascular smooth muscle
dc.subject.otherIndex Angiotensin
dc.subject.otherIndex Arrestin
dc.subject.otherIndex Biased Agonism
dc.subject.otherIndex Bradykinin
dc.subject.otherIndex G Protein-coupled Receptors (GPCR)
dc.subject.otherIndex G Proteins
dc.subject.otherIndex Heterodimerization
dc.subject.otherIndex Sequestration
dc.subject.otherIndex Signal Transduction
dc.subject.otherIndex Allosteric Site
dc.subject.otherIndex Angiotensin II
dc.subject.otherIndex Animals
dc.subject.otherIndex Aorta
dc.subject.otherIndex Arrestins
dc.subject.otherIndex Calcium
dc.subject.otherIndex Dimerization
dc.subject.otherIndex Dose-Response Relationship, Drug
dc.subject.otherIndex GTP-Binding Proteins
dc.subject.otherIndex HEK293 Cells
dc.subject.otherIndex Hemodynamics
dc.subject.otherIndex Humans
dc.subject.otherIndex Kallikreins
dc.subject.otherIndex Ligands
dc.subject.otherIndex Losartan
dc.subject.otherIndex Myocytes, Smooth Muscle
dc.subject.otherIndex Rats
dc.subject.otherIndex Rats, Sprague-Dawley
dc.subject.otherIndex Receptor, Angiotensin, Type 1
dc.subject.otherIndex Receptor, Bradykinin B2
dc.subject.otherIndex Signal Transduction
dc.subject.otherKeywordPlus KALLIKREIN-KININ SYSTEM
dc.subject.otherKeywordPlus VASCULAR SMOOTH-MUSCLE
dc.subject.otherKeywordPlus G-PROTEIN
dc.subject.otherKeywordPlus BETA-ARRESTIN
dc.subject.otherKeywordPlus NITRIC-OXIDE
dc.subject.otherKeywordPlus IN-VIVO
dc.subject.otherKeywordPlus DIABETIC-NEPHROPATHY
dc.subject.otherKeywordPlus HEART-FAILURE
dc.subject.otherKeywordPlus BIASED LIGAND
dc.subject.otherWOS Biochemistry and Molecular Biology

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