Cross-Desensitization and Cointernalization of H1 and H2 Histamine Receptors Reveal New Insights into Histamine Signal Integration

Autores
Alonso, Maria Natalia; Fernández, Natalia Brenda; Notcovich, Cintia Karina; Monczor, Federico; Simaan, May; Baldi, Alberto; Gutkind, J. Silvio; Davio, Carlos Alberto; Shayo, Carina Claudia
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
G-protein coupled receptor (GPCR) signaling does not result from sequential activation of a linear pathway of proteins/enzymes, but rather from complex interactions of multiple, branched signaling routes, ie, signaling networks. In this work we present an exhaustive study of the crosstalk between H1 and H2 histamine receptors (H1R and H2R) in U937 cells and CHO transfected cells. By desensitization assays we demonstrated the existence of a cross-desensitization between both receptors independent of protein kinase A (PKA) or C (PKC). H1R agonist stimulation inhibited cell proliferation and induced apoptosis in U937 cells following treatment for 48h. H1R-induced antiproliferative and apoptotic response was inhibited by an H2R agonist suggesting that the crosstalk between both receptors modifies their function. Binding and confocal microscopy studies revealed cointernalization of both receptors upon treatment with the agonists. In order to evaluate potential heterodimerization of the receptors, sensitized emission FRET experiments were performed in HEK293T cells using H1R-CFP and H2R-YFP. To our knowledge these findings may represent the first demonstration of agonist-induced heterodimerization of the H1R and H2R. In addition, we also show that the inhibition of the internalization process did not prevent receptor cross-desensitization which was mediated by GRK2. Our study provides new insights into the complex signaling network mediated by histamine and further knowledge for the rational use of its ligands.
Fil: Alonso, Maria Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina;
Fil: Fernández, Natalia Brenda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina;
Fil: Notcovich, Cintia Karina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina;
Fil: Monczor, Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina;
Fil: Simaan, May. National Institutes of Health; Estados Unidos de América;
Fil: Baldi, Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina;
Fil: Gutkind, J. Silvio. National Institutes of Health; Estados Unidos de América;
Fil: Davio, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina;
Fil: Shayo, Carina Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina;
Materia
HISTAMINE-RECEPTORS
HETERODIMERIZATION
COINTERNALIZATION
APOPTOSIS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/1781
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/1781
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Cross-Desensitization and Cointernalization of H1 and H2 Histamine Receptors Reveal New Insights into Histamine Signal IntegrationAlonso, Maria NataliaFernández, Natalia BrendaNotcovich, Cintia KarinaMonczor, FedericoSimaan, MayBaldi, AlbertoGutkind, J. SilvioDavio, Carlos AlbertoShayo, Carina ClaudiaHISTAMINE-RECEPTORSHETERODIMERIZATIONCOINTERNALIZATIONAPOPTOSIShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3G-protein coupled receptor (GPCR) signaling does not result from sequential activation of a linear pathway of proteins/enzymes, but rather from complex interactions of multiple, branched signaling routes, ie, signaling networks. In this work we present an exhaustive study of the crosstalk between H1 and H2 histamine receptors (H1R and H2R) in U937 cells and CHO transfected cells. By desensitization assays we demonstrated the existence of a cross-desensitization between both receptors independent of protein kinase A (PKA) or C (PKC). H1R agonist stimulation inhibited cell proliferation and induced apoptosis in U937 cells following treatment for 48h. H1R-induced antiproliferative and apoptotic response was inhibited by an H2R agonist suggesting that the crosstalk between both receptors modifies their function. Binding and confocal microscopy studies revealed cointernalization of both receptors upon treatment with the agonists. In order to evaluate potential heterodimerization of the receptors, sensitized emission FRET experiments were performed in HEK293T cells using H1R-CFP and H2R-YFP. To our knowledge these findings may represent the first demonstration of agonist-induced heterodimerization of the H1R and H2R. In addition, we also show that the inhibition of the internalization process did not prevent receptor cross-desensitization which was mediated by GRK2. Our study provides new insights into the complex signaling network mediated by histamine and further knowledge for the rational use of its ligands.Fil: Alonso, Maria Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina;Fil: Fernández, Natalia Brenda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina;Fil: Notcovich, Cintia Karina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina;Fil: Monczor, Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina;Fil: Simaan, May. National Institutes of Health; Estados Unidos de América;Fil: Baldi, Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina;Fil: Gutkind, J. Silvio. National Institutes of Health; Estados Unidos de América;Fil: Davio, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina;Fil: Shayo, Carina Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina;American Society for Pharmacology and Experimental Therapeutics2013-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/1781Alonso, Maria Natalia; Fernández, Natalia Brenda; Notcovich, Cintia Karina; Monczor, Federico; Simaan, May; et al.; Cross-Desensitization and Cointernalization of H1 and H2 Histamine Receptors Reveal New Insights into Histamine Signal Integration; American Society for Pharmacology and Experimental Therapeutics; Molecular Pharmacology; 83; 5-2013; 1087-10980026-895Xenginfo:eu-repo/semantics/reference es info:eu-repo/semantics/reference/pmid/PMID: 23462507 [PubMed - indexed for MEDLINE] PMCID: PMC3629830 Free PMC Articleinfo:eu-repo/semantics/altIdentifier/url/http://molpharm.aspetjournals.org/content/83/5/1087.full.pdf+htmlinfo:eu-repo/semantics/altIdentifier/url/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629830/info:eu-repo/semantics/altIdentifier/doi/10.1124/mol.112.083394info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:24:47Zoai:ri.conicet.gov.ar:11336/1781instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-10 13:24:47.451CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Cross-Desensitization and Cointernalization of H1 and H2 Histamine Receptors Reveal New Insights into Histamine Signal Integration
title Cross-Desensitization and Cointernalization of H1 and H2 Histamine Receptors Reveal New Insights into Histamine Signal Integration
spellingShingle Cross-Desensitization and Cointernalization of H1 and H2 Histamine Receptors Reveal New Insights into Histamine Signal Integration
Alonso, Maria Natalia
HISTAMINE-RECEPTORS
HETERODIMERIZATION
COINTERNALIZATION
APOPTOSIS
title_short Cross-Desensitization and Cointernalization of H1 and H2 Histamine Receptors Reveal New Insights into Histamine Signal Integration
title_full Cross-Desensitization and Cointernalization of H1 and H2 Histamine Receptors Reveal New Insights into Histamine Signal Integration
title_fullStr Cross-Desensitization and Cointernalization of H1 and H2 Histamine Receptors Reveal New Insights into Histamine Signal Integration
title_full_unstemmed Cross-Desensitization and Cointernalization of H1 and H2 Histamine Receptors Reveal New Insights into Histamine Signal Integration
title_sort Cross-Desensitization and Cointernalization of H1 and H2 Histamine Receptors Reveal New Insights into Histamine Signal Integration
dc.creator.none.fl_str_mv Alonso, Maria Natalia
Fernández, Natalia Brenda
Notcovich, Cintia Karina
Monczor, Federico
Simaan, May
Baldi, Alberto
Gutkind, J. Silvio
Davio, Carlos Alberto
Shayo, Carina Claudia
author Alonso, Maria Natalia
author_facet Alonso, Maria Natalia
Fernández, Natalia Brenda
Notcovich, Cintia Karina
Monczor, Federico
Simaan, May
Baldi, Alberto
Gutkind, J. Silvio
Davio, Carlos Alberto
Shayo, Carina Claudia
author_role author
author2 Fernández, Natalia Brenda
Notcovich, Cintia Karina
Monczor, Federico
Simaan, May
Baldi, Alberto
Gutkind, J. Silvio
Davio, Carlos Alberto
Shayo, Carina Claudia
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv HISTAMINE-RECEPTORS
HETERODIMERIZATION
COINTERNALIZATION
APOPTOSIS
topic HISTAMINE-RECEPTORS
HETERODIMERIZATION
COINTERNALIZATION
APOPTOSIS
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv G-protein coupled receptor (GPCR) signaling does not result from sequential activation of a linear pathway of proteins/enzymes, but rather from complex interactions of multiple, branched signaling routes, ie, signaling networks. In this work we present an exhaustive study of the crosstalk between H1 and H2 histamine receptors (H1R and H2R) in U937 cells and CHO transfected cells. By desensitization assays we demonstrated the existence of a cross-desensitization between both receptors independent of protein kinase A (PKA) or C (PKC). H1R agonist stimulation inhibited cell proliferation and induced apoptosis in U937 cells following treatment for 48h. H1R-induced antiproliferative and apoptotic response was inhibited by an H2R agonist suggesting that the crosstalk between both receptors modifies their function. Binding and confocal microscopy studies revealed cointernalization of both receptors upon treatment with the agonists. In order to evaluate potential heterodimerization of the receptors, sensitized emission FRET experiments were performed in HEK293T cells using H1R-CFP and H2R-YFP. To our knowledge these findings may represent the first demonstration of agonist-induced heterodimerization of the H1R and H2R. In addition, we also show that the inhibition of the internalization process did not prevent receptor cross-desensitization which was mediated by GRK2. Our study provides new insights into the complex signaling network mediated by histamine and further knowledge for the rational use of its ligands.
Fil: Alonso, Maria Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina;
Fil: Fernández, Natalia Brenda. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina;
Fil: Notcovich, Cintia Karina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina;
Fil: Monczor, Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina;
Fil: Simaan, May. National Institutes of Health; Estados Unidos de América;
Fil: Baldi, Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina;
Fil: Gutkind, J. Silvio. National Institutes of Health; Estados Unidos de América;
Fil: Davio, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Química Medicinal; Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina;
Fil: Shayo, Carina Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina;
description G-protein coupled receptor (GPCR) signaling does not result from sequential activation of a linear pathway of proteins/enzymes, but rather from complex interactions of multiple, branched signaling routes, ie, signaling networks. In this work we present an exhaustive study of the crosstalk between H1 and H2 histamine receptors (H1R and H2R) in U937 cells and CHO transfected cells. By desensitization assays we demonstrated the existence of a cross-desensitization between both receptors independent of protein kinase A (PKA) or C (PKC). H1R agonist stimulation inhibited cell proliferation and induced apoptosis in U937 cells following treatment for 48h. H1R-induced antiproliferative and apoptotic response was inhibited by an H2R agonist suggesting that the crosstalk between both receptors modifies their function. Binding and confocal microscopy studies revealed cointernalization of both receptors upon treatment with the agonists. In order to evaluate potential heterodimerization of the receptors, sensitized emission FRET experiments were performed in HEK293T cells using H1R-CFP and H2R-YFP. To our knowledge these findings may represent the first demonstration of agonist-induced heterodimerization of the H1R and H2R. In addition, we also show that the inhibition of the internalization process did not prevent receptor cross-desensitization which was mediated by GRK2. Our study provides new insights into the complex signaling network mediated by histamine and further knowledge for the rational use of its ligands.
publishDate 2013
dc.date.none.fl_str_mv 2013-05
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/1781
Alonso, Maria Natalia; Fernández, Natalia Brenda; Notcovich, Cintia Karina; Monczor, Federico; Simaan, May; et al.; Cross-Desensitization and Cointernalization of H1 and H2 Histamine Receptors Reveal New Insights into Histamine Signal Integration; American Society for Pharmacology and Experimental Therapeutics; Molecular Pharmacology; 83; 5-2013; 1087-1098
0026-895X
url http://hdl.handle.net/11336/1781
identifier_str_mv Alonso, Maria Natalia; Fernández, Natalia Brenda; Notcovich, Cintia Karina; Monczor, Federico; Simaan, May; et al.; Cross-Desensitization and Cointernalization of H1 and H2 Histamine Receptors Reveal New Insights into Histamine Signal Integration; American Society for Pharmacology and Experimental Therapeutics; Molecular Pharmacology; 83; 5-2013; 1087-1098
0026-895X
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/reference es info:eu-repo/semantics/reference/pmid/PMID: 23462507 [PubMed - indexed for MEDLINE] PMCID: PMC3629830 Free PMC Article
info:eu-repo/semantics/altIdentifier/url/http://molpharm.aspetjournals.org/content/83/5/1087.full.pdf+html
info:eu-repo/semantics/altIdentifier/url/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3629830/
info:eu-repo/semantics/altIdentifier/doi/10.1124/mol.112.083394
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society for Pharmacology and Experimental Therapeutics
publisher.none.fl_str_mv American Society for Pharmacology and Experimental Therapeutics
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.48226

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