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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Detalles Bibliográficos
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
Descripción
Sumario: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.

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