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J. Biol. Chem., Vol. 279, Issue 33, 34431-34439, August 13, 2004

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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^*

Carlos P. Fitzsimons, Federico Monczor¶||, Natalia Fernández¶||, Carina Shayo||**, and Carlos Davio¶||

From the ^¶Laboratorio de Radioisótopos, Facultad de Farmacia y Bioquímica, Instituto de Biología y Medicina Experimental, ^**Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and ^||Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, 1113 Argentina

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 G_q/11 protein-coupled form of the receptor and to promote a G protein-coupled inactive state of the H₁ 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 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.

Received for publication, January 22, 2004 , and in revised form, June 7, 2004.

^* This work was supported by grants from the Universidad de Buenos Aires, Fundación Antorchas, and Consejo Nacional de Investigaciones Científicas y Técnicas. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

To whom correspondence should be addressed: Laboratorio de Radioisótopos, Catedra de Fisica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junin 956, PB, Buenos Aires 1113, Argentina. Tel.: 54-11-4964-8277; Fax: 54-11-4786-2574; E-mail: cardavio{at}ffyb.uba.ar.

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