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

FITZSIMONS CARLOS; MONCZOR FEDERICO; FERNANDEZ NATALIA; SHAYO CARINA; DAVIO CARLOS

JOURNAL OF BIOLOGICAL CHEMISTRY

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Lugar: Bethesda, Maryland; Año: 2004 vol. 279 p. 34431 - 34439

0021-9258

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 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 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 G11 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 G11 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. 1 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.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 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 G11 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 G11 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. 1 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.