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

• Autores: Fitzsimons, C.P.; Monczor, F.; Fernández, N.; Shayo, C.; Davio, C.
• Año de publicación: 2004
• Idioma: inglés
• Tipo de recurso: artículo
• Fuente: J. Biol. Chem. 2004;279(33):34431-34439
• Materia: 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
• Institución: Universidad Nacional de Buenos Aires. Facultad de Ciencias Exactas y Naturales

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.