Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary c...

Autores
Monczor, Federico; Fernandez, Natalia Cristina; Lemos Legnazzi, Bibiana; Riveiro, Maria Eugenia; Baldi, Alberto; Shayo, Carina Claudia; Davio, Carlos Alberto
Año de publicación
2003
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Knowing the importance for research and pharmacological uses of proper ligand classification into agonists, inverse agonists, and antagonists, the aim of this work was to study the behavior of tiotidine, a controversial histamine H2 receptor ligand. We found that tiotidine, described previously as an H2 antagonist, actually behaves as an inverse agonist in U-937 cells, diminishing basal cAMP levels. [3H]Tiotidine showed two binding sites, one with high affinity and low capacity and the other with low affinity and high capacity. The former site disappeared in the presence of guanosine 5'-O-(3-thio)triphosphate, indicating that it belongs to a subset of receptors coupled to G-protein, showing the classic binding profile for an agonist. Considering the occupancy models developed up to now, the only one that explains tiotidine dual behavior is the cubic ternary complex (CTC) model. This model allows G-protein to interact with the receptor even in the inactive state. We showed by theoretical simulations based on the CTC model of dose-response and binding experiments that tiotidine biases the system to a G-protein-coupled form of the receptor that is unable to evoke a response. This theoretical approach was supported by experimental results in which an unrelated G-protein-coupled receptor that also signals through Galphas-protein (beta2-adrenoreceptor) was impeded by tiotidine. This interference clearly implies that tiotidine biases the system to Galphas-coupled form of the H2 receptor and turns Galphas-protein less available to interact with beta2-adrenoreceptor. These findings not only show that tiotidine is an H2 inverse agonist in U-937 cells but also provide experimental support for the CTC model.
Fil: Monczor, Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
Fil: Fernandez, Natalia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Lemos Legnazzi, Bibiana. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
Fil: Riveiro, Maria Eugenia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
Fil: Baldi, Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Shayo, Carina Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina
Fil: Davio, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
Materia
Histamine Receptors
Inverse Agonist
Tiotidine
Camp
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:11336/36406
Acceder
id CONICETDig_79f8e442d6bc10f225dc8b271812ba16
oai_identifier_str oai:ri.conicet.gov.ar:11336/36406
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model.Monczor, FedericoFernandez, Natalia CristinaLemos Legnazzi, BibianaRiveiro, Maria EugeniaBaldi, AlbertoShayo, Carina ClaudiaDavio, Carlos AlbertoHistamine ReceptorsInverse AgonistTiotidineCamphttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Knowing the importance for research and pharmacological uses of proper ligand classification into agonists, inverse agonists, and antagonists, the aim of this work was to study the behavior of tiotidine, a controversial histamine H2 receptor ligand. We found that tiotidine, described previously as an H2 antagonist, actually behaves as an inverse agonist in U-937 cells, diminishing basal cAMP levels. [3H]Tiotidine showed two binding sites, one with high affinity and low capacity and the other with low affinity and high capacity. The former site disappeared in the presence of guanosine 5'-O-(3-thio)triphosphate, indicating that it belongs to a subset of receptors coupled to G-protein, showing the classic binding profile for an agonist. Considering the occupancy models developed up to now, the only one that explains tiotidine dual behavior is the cubic ternary complex (CTC) model. This model allows G-protein to interact with the receptor even in the inactive state. We showed by theoretical simulations based on the CTC model of dose-response and binding experiments that tiotidine biases the system to a G-protein-coupled form of the receptor that is unable to evoke a response. This theoretical approach was supported by experimental results in which an unrelated G-protein-coupled receptor that also signals through Galphas-protein (beta2-adrenoreceptor) was impeded by tiotidine. This interference clearly implies that tiotidine biases the system to Galphas-coupled form of the H2 receptor and turns Galphas-protein less available to interact with beta2-adrenoreceptor. These findings not only show that tiotidine is an H2 inverse agonist in U-937 cells but also provide experimental support for the CTC model.Fil: Monczor, Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Fernandez, Natalia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Lemos Legnazzi, Bibiana. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Riveiro, Maria Eugenia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Baldi, Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Shayo, Carina Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; ArgentinaFil: Davio, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaAmerican Society for Pharmacology and Experimental Therapeutics2003-08-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/36406Monczor, Federico; Fernandez, Natalia Cristina; Lemos Legnazzi, Bibiana; Riveiro, Maria Eugenia; Baldi, Alberto; et al.; Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model.; American Society for Pharmacology and Experimental Therapeutics; Molecular Pharmacology; 64; 2; 1-8-2003; 512-5200026-895XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://molpharm.aspetjournals.org/content/64/2/512.shortinfo:eu-repo/semantics/altIdentifier/doi/10.1124/mol.64.2.512info:eu-repo/semantics/altIdentifier/pmid/12869657info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:10:22Zoai:ri.conicet.gov.ar:11336/36406instacron: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:34982025-09-03 10:10:22.289CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model.
title Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model.
spellingShingle Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model.
Monczor, Federico
Histamine Receptors
Inverse Agonist
Tiotidine
Camp
title_short Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model.
title_full Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model.
title_fullStr Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model.
title_full_unstemmed Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model.
title_sort Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model.
dc.creator.none.fl_str_mv Monczor, Federico
Fernandez, Natalia Cristina
Lemos Legnazzi, Bibiana
Riveiro, Maria Eugenia
Baldi, Alberto
Shayo, Carina Claudia
Davio, Carlos Alberto
author Monczor, Federico
author_facet Monczor, Federico
Fernandez, Natalia Cristina
Lemos Legnazzi, Bibiana
Riveiro, Maria Eugenia
Baldi, Alberto
Shayo, Carina Claudia
Davio, Carlos Alberto
author_role author
author2 Fernandez, Natalia Cristina
Lemos Legnazzi, Bibiana
Riveiro, Maria Eugenia
Baldi, Alberto
Shayo, Carina Claudia
Davio, Carlos Alberto
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Histamine Receptors
Inverse Agonist
Tiotidine
Camp
topic Histamine Receptors
Inverse Agonist
Tiotidine
Camp
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Knowing the importance for research and pharmacological uses of proper ligand classification into agonists, inverse agonists, and antagonists, the aim of this work was to study the behavior of tiotidine, a controversial histamine H2 receptor ligand. We found that tiotidine, described previously as an H2 antagonist, actually behaves as an inverse agonist in U-937 cells, diminishing basal cAMP levels. [3H]Tiotidine showed two binding sites, one with high affinity and low capacity and the other with low affinity and high capacity. The former site disappeared in the presence of guanosine 5'-O-(3-thio)triphosphate, indicating that it belongs to a subset of receptors coupled to G-protein, showing the classic binding profile for an agonist. Considering the occupancy models developed up to now, the only one that explains tiotidine dual behavior is the cubic ternary complex (CTC) model. This model allows G-protein to interact with the receptor even in the inactive state. We showed by theoretical simulations based on the CTC model of dose-response and binding experiments that tiotidine biases the system to a G-protein-coupled form of the receptor that is unable to evoke a response. This theoretical approach was supported by experimental results in which an unrelated G-protein-coupled receptor that also signals through Galphas-protein (beta2-adrenoreceptor) was impeded by tiotidine. This interference clearly implies that tiotidine biases the system to Galphas-coupled form of the H2 receptor and turns Galphas-protein less available to interact with beta2-adrenoreceptor. These findings not only show that tiotidine is an H2 inverse agonist in U-937 cells but also provide experimental support for the CTC model.
Fil: Monczor, Federico. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
Fil: Fernandez, Natalia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Lemos Legnazzi, Bibiana. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
Fil: Riveiro, Maria Eugenia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
Fil: Baldi, Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Shayo, Carina Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Fisiología, Biología Molecular y Celular; Argentina
Fil: Davio, Carlos Alberto. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina
description Knowing the importance for research and pharmacological uses of proper ligand classification into agonists, inverse agonists, and antagonists, the aim of this work was to study the behavior of tiotidine, a controversial histamine H2 receptor ligand. We found that tiotidine, described previously as an H2 antagonist, actually behaves as an inverse agonist in U-937 cells, diminishing basal cAMP levels. [3H]Tiotidine showed two binding sites, one with high affinity and low capacity and the other with low affinity and high capacity. The former site disappeared in the presence of guanosine 5'-O-(3-thio)triphosphate, indicating that it belongs to a subset of receptors coupled to G-protein, showing the classic binding profile for an agonist. Considering the occupancy models developed up to now, the only one that explains tiotidine dual behavior is the cubic ternary complex (CTC) model. This model allows G-protein to interact with the receptor even in the inactive state. We showed by theoretical simulations based on the CTC model of dose-response and binding experiments that tiotidine biases the system to a G-protein-coupled form of the receptor that is unable to evoke a response. This theoretical approach was supported by experimental results in which an unrelated G-protein-coupled receptor that also signals through Galphas-protein (beta2-adrenoreceptor) was impeded by tiotidine. This interference clearly implies that tiotidine biases the system to Galphas-coupled form of the H2 receptor and turns Galphas-protein less available to interact with beta2-adrenoreceptor. These findings not only show that tiotidine is an H2 inverse agonist in U-937 cells but also provide experimental support for the CTC model.
publishDate 2003
dc.date.none.fl_str_mv 2003-08-01
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/11336/36406
Monczor, Federico; Fernandez, Natalia Cristina; Lemos Legnazzi, Bibiana; Riveiro, Maria Eugenia; Baldi, Alberto; et al.; Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model.; American Society for Pharmacology and Experimental Therapeutics; Molecular Pharmacology; 64; 2; 1-8-2003; 512-520
0026-895X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/36406
identifier_str_mv Monczor, Federico; Fernandez, Natalia Cristina; Lemos Legnazzi, Bibiana; Riveiro, Maria Eugenia; Baldi, Alberto; et al.; Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model.; American Society for Pharmacology and Experimental Therapeutics; Molecular Pharmacology; 64; 2; 1-8-2003; 512-520
0026-895X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://molpharm.aspetjournals.org/content/64/2/512.short
info:eu-repo/semantics/altIdentifier/doi/10.1124/mol.64.2.512
info:eu-repo/semantics/altIdentifier/pmid/12869657
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
application/pdf
application/pdf
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
_version_ 1842270116622893056
score 13.13397

Publicaciones similares