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Abstract:

Bradykinin B2 receptor (B2R) and angiotensin-(1-7) Mas receptor (MasR)-mediated effects are physiologically interconnected. The molecular basis for such cross talk is unknown. It is hypothesized that the cross talk occurs at the receptor level. We investigated B2R-MasR heteromerization and the functional consequences of such interaction. B2R fused to the cyan fluorescent protein and MasR fused to the yellow fluorescent protein were transiently coexpressed in human embryonic kidney293T cells. Fluorescence resonance energy transfer analysis showed that B2R and MasR formed a constitutive heteromer, which was not modified by their agonists. B2R or MasR antagonists decreased fluorescence resonance energy transfer efficiency, suggesting that the antagonist promoted heteromer dissociation. B2R-MasR heteromerization induced an 8-fold increase in the MasR ligand-binding affinity. On agonist stimulation, the heteromer was internalized into early endosomes with a slower sequestration rate from the plasma membrane, compared with single receptors. B2R-MasR heteromerization induced a greater increase in arachidonic acid release and extracellular signal-regulated kinase phosphorylation after angiotensin-(1-7) stimulation, and this effect was blocked by the B2R antagonist. Concerning serine/threonine kinase Akt activity, a significant bradykinin-promoted activation was detected in B2R-MasR but not in B2R-expressing cells. Angiotensin-(1-7) and bradykinin elicited antiproliferative effects only in cells expressing B2R-MasR heteromers, but not in cells expressing each receptor alone. Proximity ligation assay confirmed B2R-MasR interaction in human glomerular endothelial cells supporting the interaction between both receptors in vivo. Our findings provide an explanation for the cross talk between bradykinin B2R and angiotensin-(1-7) MasR-mediated effects. B2R-MasR heteromerization induces functional changes in the receptor that may lead to long-lasting protective properties. © 2016 American Heart Association, Inc.

Registro:

Documento: Artículo
Título:Heteromerization between the Bradykinin B2 Receptor and the Angiotensin-(1-7) Mas Receptor: Functional Consequences
Autor:Cerrato, B.D.; Carretero, O.A.; Janic, B.; Grecco, H.E.; Gironacci, M.M.
Filiación:Departamento de Química Biológica, IQUIFIB-CONICET, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, Buenos Aires, 1113, Argentina
Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, MI, United States
Departamento de Física, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IFIBA-CONICET, Argentina
Palabras clave:B2 receptor; heteromerization; Mas receptor; angiotensin[1-7]; arachidonic acid; bradykinin; bradykinin B2 receptor; cyan fluorescent protein; mitogen activated protein kinase; protein serine threonine kinase; yellow fluorescent protein; angiotensin I; angiotensin I (1-7); bradykinin B2 receptor; bradykinin B2 receptor antagonist; mitogen activated protein kinase; peptide fragment; antiproliferative activity; Article; binding affinity; cell membrane; controlled study; dissociation; embryo; endosome; enzyme activity; enzyme phosphorylation; fluorescence resonance energy transfer; HEK293 cell line; human; human cell; priority journal; protein protein interaction; signal transduction; analysis of variance; animal; cell culture; drug effects; genetic transfection; metabolism; physiology; rat; renin angiotensin aldosterone system; sensitivity and specificity; Analysis of Variance; Angiotensin I; Animals; Bradykinin B2 Receptor Antagonists; Cell Membrane; Cells, Cultured; Extracellular Signal-Regulated MAP Kinases; HEK293 Cells; Humans; Peptide Fragments; Rats; Receptor Cross-Talk; Receptor, Bradykinin B2; Renin-Angiotensin System; Sensitivity and Specificity; Transfection
Año:2016
Volumen:68
Número:4
Página de inicio:1039
Página de fin:1048
DOI: http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.07874
Título revista:Hypertension
Título revista abreviado:Hypertension
ISSN:0194911X
CODEN:HPRTD
CAS:angiotensin[1-7], 39386-80-6; arachidonic acid, 506-32-1, 6610-25-9, 7771-44-0; bradykinin, 58-82-2, 5979-11-3; mitogen activated protein kinase, 142243-02-5; protein serine threonine kinase; angiotensin I, 9041-90-1; Angiotensin I; angiotensin I (1-7); Bradykinin B2 Receptor Antagonists; Extracellular Signal-Regulated MAP Kinases; Peptide Fragments; Receptor, Bradykinin B2
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0194911X_v68_n4_p1039_Cerrato

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Citas:

---------- APA ----------
Cerrato, B.D., Carretero, O.A., Janic, B., Grecco, H.E. & Gironacci, M.M. (2016) . Heteromerization between the Bradykinin B2 Receptor and the Angiotensin-(1-7) Mas Receptor: Functional Consequences. Hypertension, 68(4), 1039-1048.
http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.07874
---------- CHICAGO ----------
Cerrato, B.D., Carretero, O.A., Janic, B., Grecco, H.E., Gironacci, M.M. "Heteromerization between the Bradykinin B2 Receptor and the Angiotensin-(1-7) Mas Receptor: Functional Consequences" . Hypertension 68, no. 4 (2016) : 1039-1048.
http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.07874
---------- MLA ----------
Cerrato, B.D., Carretero, O.A., Janic, B., Grecco, H.E., Gironacci, M.M. "Heteromerization between the Bradykinin B2 Receptor and the Angiotensin-(1-7) Mas Receptor: Functional Consequences" . Hypertension, vol. 68, no. 4, 2016, pp. 1039-1048.
http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.07874
---------- VANCOUVER ----------
Cerrato, B.D., Carretero, O.A., Janic, B., Grecco, H.E., Gironacci, M.M. Heteromerization between the Bradykinin B2 Receptor and the Angiotensin-(1-7) Mas Receptor: Functional Consequences. Hypertension. 2016;68(4):1039-1048.
http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.07874