Mepyramine, a histamine H1 receptor inverse agonist, binds preferentially to a G protein-coupled form of the receptor and sequesters G protein

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Accurate characterization of the molecular mechanisms of the action of ligands is an extremely important issue for their appropriate research, pharmacological, and therapeutic uses. In view of this fact, the aim of the present work was to investigate the mechanisms involved in the actions of mepyram...

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Autores principales:	Fitzsimons, C.P., Monczor, F., Fernández, N., Shayo, C., Davio, C.
Formato:	Artículo publishedVersion
Lenguaje:	Inglés
Publicado:	2004
Materias:	Adenosinetriphosphate Biochemistry Calcium Cells Proteins Mepyramine Molecular mechanisms Pharmacology Signaling pathways Drug products calcium G protein coupled receptor histamine H1 receptor mepyramine purine receptor adenosine triphosphate guanine nucleotide binding protein guanine nucleotide binding protein alpha subunit guanosine 5' o (3 thiotriphosphate) histamine H1 receptor antagonist inositol phosphate ligand triprolidine animal cell article calcium blood level Chinese hamster CHO cell controlled study drug mechanism guinea pig molecular model nonhuman nucleotide sequence priority journal protein expression receptor affinity signal transduction animal cell membrane chemical model chemistry dose response hamster metabolism molecular cloning protein binding Western blotting Animalia Cavia porcellus Cricetinae Cricetulus griseus Sus scrofa Adenosine Triphosphate Animals Blotting, Western Cell Membrane CHO Cells Cloning, Molecular Dose-Response Relationship, Drug GTP-Binding Protein alpha Subunits, Gq-G11 GTP-Binding Proteins Guanosine 5'-O-(3-Thiotriphosphate) Guinea Pigs Histamine H1 Antagonists Inositol Phosphates Ligands Models, Chemical Protein Binding Pyrilamine Receptors, Histamine H1 Triprolidine
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_00219258_v279_n33_p34431_Fitzsimons
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	paperaa:paper_00219258_v279_n33_p34431_Fitzsimons
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spelling	paperaa:paper_00219258_v279_n33_p34431_Fitzsimons2023-06-12T16:42:52Z Mepyramine, a histamine H1 receptor inverse agonist, binds preferentially to a G protein-coupled form of the receptor and sequesters G protein J. Biol. Chem. 2004;279(33):34431-34439 Fitzsimons, C.P. Monczor, F. Fernández, N. Shayo, C. Davio, C. Adenosinetriphosphate Biochemistry Calcium Cells Proteins Mepyramine Molecular mechanisms Pharmacology Signaling pathways Drug products calcium G protein coupled receptor histamine H1 receptor mepyramine purine receptor adenosine triphosphate calcium guanine nucleotide binding protein guanine nucleotide binding protein alpha subunit guanosine 5' o (3 thiotriphosphate) histamine H1 receptor histamine H1 receptor antagonist inositol phosphate ligand triprolidine animal cell article calcium blood level Chinese hamster CHO cell controlled study drug mechanism guinea pig molecular model nonhuman nucleotide sequence priority journal protein expression receptor affinity signal transduction animal cell membrane chemical model chemistry dose response hamster metabolism molecular cloning protein binding Western blotting Animalia Cavia porcellus Cricetinae Cricetulus griseus Sus scrofa Adenosine Triphosphate Animals Blotting, Western Calcium Cell Membrane CHO Cells Cloning, Molecular Cricetinae Dose-Response Relationship, Drug GTP-Binding Protein alpha Subunits, Gq-G11 GTP-Binding Proteins Guanosine 5'-O-(3-Thiotriphosphate) Guinea Pigs Histamine H1 Antagonists Inositol Phosphates Ligands Models, Chemical Protein Binding Pyrilamine Receptors, Histamine H1 Triprolidine Accurate characterization of the molecular mechanisms of the action of ligands is an extremely important issue for their appropriate research, pharmacological, and therapeutic uses. In view of this fact, the aim of the present work was to investigate the mechanisms involved in the actions of mepyramine at the guinea pig H1 receptor stably expressed in Chinese hamster ovary cells. We found that mepyramine is able to decrease the basal constitutive activity of the guinea pig H1 receptor, to bind with high affinity to a Gq/11 protein-coupled form of the receptor and to promote a G protein-coupled inactive state of the H1 receptor that interferes with the Gq/11-mediated signaling of the endogenously expressed ATP receptor, as predicted by the Cubic Ternary Complex Model of receptor occupancy. The effect of mepyramine on ATP-induced signaling was specifically neutralized by Gα11 overexpression, indicating that mepyramine is able to reduce G protein availability for other non-related receptors associated with the same signaling pathway. Finally, we found a loss of mepyramine efficacy in decreasing basal levels of intracellular calcium at high Gα11 expression levels, which can be theoretically explained in terms of high H1 receptor constitutive activity. The whole of the present work sheds new light on H1 receptor pharmacology and the mechanisms H1 receptor inverse agonists could use to exert their observed negative efficacy. Fil:Fernández, N. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Shayo, C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2004 info:eu-repo/semantics/article info:ar-repo/semantics/artículo info:eu-repo/semantics/publishedVersion application/pdf eng info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00219258_v279_n33_p34431_Fitzsimons
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
language	Inglés
orig_language_str_mv	eng
topic	Adenosinetriphosphate Biochemistry Calcium Cells Proteins Mepyramine Molecular mechanisms Pharmacology Signaling pathways Drug products calcium G protein coupled receptor histamine H1 receptor mepyramine purine receptor adenosine triphosphate calcium guanine nucleotide binding protein guanine nucleotide binding protein alpha subunit guanosine 5' o (3 thiotriphosphate) histamine H1 receptor histamine H1 receptor antagonist inositol phosphate ligand triprolidine animal cell article calcium blood level Chinese hamster CHO cell controlled study drug mechanism guinea pig molecular model nonhuman nucleotide sequence priority journal protein expression receptor affinity signal transduction animal cell membrane chemical model chemistry dose response hamster metabolism molecular cloning protein binding Western blotting Animalia Cavia porcellus Cricetinae Cricetulus griseus Sus scrofa Adenosine Triphosphate Animals Blotting, Western Calcium Cell Membrane CHO Cells Cloning, Molecular Cricetinae Dose-Response Relationship, Drug GTP-Binding Protein alpha Subunits, Gq-G11 GTP-Binding Proteins Guanosine 5'-O-(3-Thiotriphosphate) Guinea Pigs Histamine H1 Antagonists Inositol Phosphates Ligands Models, Chemical Protein Binding Pyrilamine Receptors, Histamine H1 Triprolidine
spellingShingle	Adenosinetriphosphate Biochemistry Calcium Cells Proteins Mepyramine Molecular mechanisms Pharmacology Signaling pathways Drug products calcium G protein coupled receptor histamine H1 receptor mepyramine purine receptor adenosine triphosphate calcium guanine nucleotide binding protein guanine nucleotide binding protein alpha subunit guanosine 5' o (3 thiotriphosphate) histamine H1 receptor histamine H1 receptor antagonist inositol phosphate ligand triprolidine animal cell article calcium blood level Chinese hamster CHO cell controlled study drug mechanism guinea pig molecular model nonhuman nucleotide sequence priority journal protein expression receptor affinity signal transduction animal cell membrane chemical model chemistry dose response hamster metabolism molecular cloning protein binding Western blotting Animalia Cavia porcellus Cricetinae Cricetulus griseus Sus scrofa Adenosine Triphosphate Animals Blotting, Western Calcium Cell Membrane CHO Cells Cloning, Molecular Cricetinae Dose-Response Relationship, Drug GTP-Binding Protein alpha Subunits, Gq-G11 GTP-Binding Proteins Guanosine 5'-O-(3-Thiotriphosphate) Guinea Pigs Histamine H1 Antagonists Inositol Phosphates Ligands Models, Chemical Protein Binding Pyrilamine Receptors, Histamine H1 Triprolidine Fitzsimons, C.P. Monczor, F. Fernández, N. Shayo, C. Davio, C. Mepyramine, a histamine H1 receptor inverse agonist, binds preferentially to a G protein-coupled form of the receptor and sequesters G protein
topic_facet	Adenosinetriphosphate Biochemistry Calcium Cells Proteins Mepyramine Molecular mechanisms Pharmacology Signaling pathways Drug products calcium G protein coupled receptor histamine H1 receptor mepyramine purine receptor adenosine triphosphate calcium guanine nucleotide binding protein guanine nucleotide binding protein alpha subunit guanosine 5' o (3 thiotriphosphate) histamine H1 receptor histamine H1 receptor antagonist inositol phosphate ligand triprolidine animal cell article calcium blood level Chinese hamster CHO cell controlled study drug mechanism guinea pig molecular model nonhuman nucleotide sequence priority journal protein expression receptor affinity signal transduction animal cell membrane chemical model chemistry dose response hamster metabolism molecular cloning protein binding Western blotting Animalia Cavia porcellus Cricetinae Cricetulus griseus Sus scrofa Adenosine Triphosphate Animals Blotting, Western Calcium Cell Membrane CHO Cells Cloning, Molecular Cricetinae Dose-Response Relationship, Drug GTP-Binding Protein alpha Subunits, Gq-G11 GTP-Binding Proteins Guanosine 5'-O-(3-Thiotriphosphate) Guinea Pigs Histamine H1 Antagonists Inositol Phosphates Ligands Models, Chemical Protein Binding Pyrilamine Receptors, Histamine H1 Triprolidine
description	Accurate characterization of the molecular mechanisms of the action of ligands is an extremely important issue for their appropriate research, pharmacological, and therapeutic uses. In view of this fact, the aim of the present work was to investigate the mechanisms involved in the actions of mepyramine at the guinea pig H1 receptor stably expressed in Chinese hamster ovary cells. We found that mepyramine is able to decrease the basal constitutive activity of the guinea pig H1 receptor, to bind with high affinity to a Gq/11 protein-coupled form of the receptor and to promote a G protein-coupled inactive state of the H1 receptor that interferes with the Gq/11-mediated signaling of the endogenously expressed ATP receptor, as predicted by the Cubic Ternary Complex Model of receptor occupancy. The effect of mepyramine on ATP-induced signaling was specifically neutralized by Gα11 overexpression, indicating that mepyramine is able to reduce G protein availability for other non-related receptors associated with the same signaling pathway. Finally, we found a loss of mepyramine efficacy in decreasing basal levels of intracellular calcium at high Gα11 expression levels, which can be theoretically explained in terms of high H1 receptor constitutive activity. The whole of the present work sheds new light on H1 receptor pharmacology and the mechanisms H1 receptor inverse agonists could use to exert their observed negative efficacy.
format	Artículo Artículo publishedVersion
author	Fitzsimons, C.P. Monczor, F. Fernández, N. Shayo, C. Davio, C.
author_facet	Fitzsimons, C.P. Monczor, F. Fernández, N. Shayo, C. Davio, C.
author_sort	Fitzsimons, C.P.
title	Mepyramine, a histamine H1 receptor inverse agonist, binds preferentially to a G protein-coupled form of the receptor and sequesters G protein
title_short	Mepyramine, a histamine H1 receptor inverse agonist, binds preferentially to a G protein-coupled form of the receptor and sequesters G protein
title_full	Mepyramine, a histamine H1 receptor inverse agonist, binds preferentially to a G protein-coupled form of the receptor and sequesters G protein
title_fullStr	Mepyramine, a histamine H1 receptor inverse agonist, binds preferentially to a G protein-coupled form of the receptor and sequesters G protein
title_full_unstemmed	Mepyramine, a histamine H1 receptor inverse agonist, binds preferentially to a G protein-coupled form of the receptor and sequesters G protein
title_sort	mepyramine, a histamine h1 receptor inverse agonist, binds preferentially to a g protein-coupled form of the receptor and sequesters g protein
publishDate	2004
url	http://hdl.handle.net/20.500.12110/paper_00219258_v279_n33_p34431_Fitzsimons
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Mepyramine, a histamine H1 receptor inverse agonist, binds preferentially to a G protein-coupled form of the receptor and sequesters G protein

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