Estudio de los mecanismos de señalización asociados al receptor Mas

The Mas receptor (MasR) is a class A Orphan G-protein-coupled receptor (GPCR). Although angiotensin-(1-7) [Ang-(1-7)] has been reported as its putative ligand, the intracellular signaling pathways activated by the MasR remain only partially characterized. In this study we examined MasR-dependent act...

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Autor principal: Burghi, Valeria
Otros Autores: Fernández, Natalia C.
Formato: Tesis doctoral acceptedVersion
Lenguaje:Español
Publicado: Facultad de Farmacia y Bioquímica 2018
Materias:
Receptor
Señalización
Hormona
Ciencia de la vida
Acceso en línea:http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_2673
http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_2673.dir/2673.PDF
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Repositorio Digital de la Universidad de Buenos Aires (UBA) de Universidad de Buenos Aires
id I28-R145-HWA_2673
record_format dspace
spelling I28-R145-HWA_26732020-08-07 The Mas receptor (MasR) is a class A Orphan G-protein-coupled receptor (GPCR). Although angiotensin-(1-7) [Ang-(1-7)] has been reported as its putative ligand, the intracellular signaling pathways activated by the MasR remain only partially characterized. In this study we examined MasR-dependent activation of G protein-mediated and ERK mediated signaling pathways. Transfection of HEK293T cells with a wild-type MasR (wt-MasR) construct resulted in a decrease in basal cAMP levels that depended on the amount of wt-MasR protein expressed and was also observed when increasing amounts of mutant MasR lacking the PDZ binding motif were expressed. Pretreatment of wt-MasR expressing cells with pertussis toxin restored basal cAMP levels. Also, cAMP production after forskolin stimulation was lower in cells expressing wt-MasR than in control cells. These results indicate a high level of constitutive receptor activity towards cAMP modulation involving G?i-protein. Treatment with Ang(1-7) increased p-ERK levels in both wt-MasR and in mock-transfected HEK293T cells. MasR-overexpression lowered this effect. In view of these results we analized endogenous receptors expression different from MasR that could be mediating Ang-(1-7) effect. As MasR has been suggested to participate in cardiovascular and renal functions, comprehensive pharmacological characterization of MasR signaling is essential for developing clinical therapeutics targeting MasR function. Fil: Burghi, Valeria. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Buenos Aires, Argentina Fernández, Natalia C. Facultad de Farmacia y Bioquímica Dominici, Fernando P. Burghi, Valeria 2018-03-27 El receptor Mas (MasR) es un receptor de membrana acoplado a proteínas G (GPCR) que ha sido incluído dentro del grupo de GPCRs de tipo A huérfanos. A pesar de que la hormona peptídica angiotensina-(1?7) [Ang-(1?7)] perteneciente al sistema renina-angiotensina (SRA) ha sido propuesta como su ligando endógeno, la clasificación del MasR no ha sido modificada. En este trabajo de tesis se presentan resultados enfocados en dilucidar la participación de las vías de señalización dependientes de proteínas G y dependientes de kinasas activadas por mitógenos (MAPK) en la respuesta del MasR. En particular, se demostró que el MasR es capaz de modular los niveles de AMPc de forma constitutiva y mediante la activación de la proteína G?i. La Ang-(1-7) y un agonista sintético AVE 0991 actuaron como agonistas para esta vía. Sin embargo, la Ang-(1-7) no fue capaz de activar la vía G?q. Por otro lado, esta hormona provocó la fosforilación de ERK1/2 en células HEK293 control y el MasR atenuó este efecto. Debido a la presencia endógena del receptor de angiotensina II de tipo 1 en dichas células, podría postularse que el MasR ejerce una modulación negativa sobre dicha vía. application/pdf Höcht,Christian Varone, Cecilia Raingo, Jésica Receptor Señalización Hormona spa Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by-nc-nd/2.5/ar/ Ciencia de la vida Estudio de los mecanismos de señalización asociados al receptor Mas info:eu-repo/semantics/doctoralThesis info:ar-repo/semantics/tesis doctoral info:eu-repo/semantics/acceptedVersion http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_2673 http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_2673.dir/2673.PDF
institution Universidad de Buenos Aires
institution_str I-28
repository_str R-145
collection Repositorio Digital de la Universidad de Buenos Aires (UBA)
language Español
orig_language_str_mv spa
topic Receptor
Señalización
Hormona
Ciencia de la vida
spellingShingle Receptor
Señalización
Hormona
Ciencia de la vida
Burghi, Valeria
Estudio de los mecanismos de señalización asociados al receptor Mas
topic_facet Receptor
Señalización
Hormona
Ciencia de la vida
description The Mas receptor (MasR) is a class A Orphan G-protein-coupled receptor (GPCR). Although angiotensin-(1-7) [Ang-(1-7)] has been reported as its putative ligand, the intracellular signaling pathways activated by the MasR remain only partially characterized. In this study we examined MasR-dependent activation of G protein-mediated and ERK mediated signaling pathways. Transfection of HEK293T cells with a wild-type MasR (wt-MasR) construct resulted in a decrease in basal cAMP levels that depended on the amount of wt-MasR protein expressed and was also observed when increasing amounts of mutant MasR lacking the PDZ binding motif were expressed. Pretreatment of wt-MasR expressing cells with pertussis toxin restored basal cAMP levels. Also, cAMP production after forskolin stimulation was lower in cells expressing wt-MasR than in control cells. These results indicate a high level of constitutive receptor activity towards cAMP modulation involving G?i-protein. Treatment with Ang(1-7) increased p-ERK levels in both wt-MasR and in mock-transfected HEK293T cells. MasR-overexpression lowered this effect. In view of these results we analized endogenous receptors expression different from MasR that could be mediating Ang-(1-7) effect. As MasR has been suggested to participate in cardiovascular and renal functions, comprehensive pharmacological characterization of MasR signaling is essential for developing clinical therapeutics targeting MasR function.
author2 Fernández, Natalia C.
author_facet Fernández, Natalia C.
Burghi, Valeria
format Tesis doctoral
Tesis doctoral
acceptedVersion
author Burghi, Valeria
author_sort Burghi, Valeria
title Estudio de los mecanismos de señalización asociados al receptor Mas
title_short Estudio de los mecanismos de señalización asociados al receptor Mas
title_full Estudio de los mecanismos de señalización asociados al receptor Mas
title_fullStr Estudio de los mecanismos de señalización asociados al receptor Mas
title_full_unstemmed Estudio de los mecanismos de señalización asociados al receptor Mas
title_sort estudio de los mecanismos de señalización asociados al receptor mas
publisher Facultad de Farmacia y Bioquímica
publishDate 2018
url http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_2673
http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_2673.dir/2673.PDF
work_keys_str_mv AT burghivaleria estudiodelosmecanismosdesenalizacionasociadosalreceptormas
_version_ 1766017508426383360

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