Artículo
Mepyramine, a histamine H1 receptor inverse agonist, binds preferentially to a G protein-coupled form of the receptor and sequesters G protein
Fitzsimons, Carlos P.; Monczor, Federico
; Fernandez, Natalia Cristina
; Shayo, Carina Claudia
; Davio, Carlos Alberto
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Fecha de publicación:
2004
Editorial:
American Society for Biochemistry and Molecular Biology
Revista:
Journal of Biological Chemistry (online)
ISSN:
0021-9258
e-ISSN:
1083-351X
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
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 H(1) receptor stably expressed in Chinese hamster ovary cells. We found that mepyramine is able to decrease the basal constitutive activity of the guinea pig H(1) receptor, to bind with high affinity to a G(q/11) protein-coupled form of the receptor and to promote a G protein-coupled inactive state of the H(1) receptor that interferes with the G(q/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 Galpha(11) 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 Galpha(11) expression levels, which can be theoretically explained in terms of high H(1) receptor constitutive activity. The whole of the present work sheds new light on H(1) receptor pharmacology and the mechanisms H(1) receptor inverse agonists could use to exert their observed negative efficacy.
Palabras clave:
Calcium
,
Gtp Binding Proteins
,
Cell Membrane
,
Histamine H1
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Colecciones
Articulos(IBYME)
Articulos de INST.DE BIOLOGIA Y MEDICINA EXPERIMENTAL (I)
Articulos de INST.DE BIOLOGIA Y MEDICINA EXPERIMENTAL (I)
Articulos(OCA HOUSSAY)
Articulos de OFICINA DE COORDINACION ADMINISTRATIVA HOUSSAY
Articulos de OFICINA DE COORDINACION ADMINISTRATIVA HOUSSAY
Citación
Fitzsimons, Carlos P. ; Monczor, Federico; Fernandez, Natalia Cristina; Shayo, Carina Claudia; Davio, Carlos Alberto; Mepyramine, a histamine H1 receptor inverse agonist, binds preferentially to a G protein-coupled form of the receptor and sequesters G protein; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 279; 33; -1-2004; 34431-34439
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