The present address of Dr. M. J. Smit is Department of Pharmacology, Mount Sinai School of Medicine, New York, NY 10029, U.S.A.
Constitutive Activity and Structural Instability of the Wild-Type Human H2 Receptor
Article first published online: 13 NOV 2002
Journal of Neurochemistry
Volume 71, Issue 2, pages 799–807, August 1998
How to Cite
Alewijnse, A. E., Smit, M. J., Hoffmann, M., Verzijl, D., Timmerman, H. and Leurs, R. (1998), Constitutive Activity and Structural Instability of the Wild-Type Human H2 Receptor. Journal of Neurochemistry, 71: 799–807. doi: 10.1046/j.1471-4159.1998.71020799.x
- Issue published online: 13 NOV 2002
- Article first published online: 13 NOV 2002
- Received September 29, 1997; revised manuscript received January 15, 1998; accepted February 25, 1998.
- Constitutive activity;
- Histamine H2 receptor;
- Structural instability;
- Inverse agonism;
Abstract: Stable expression of the human H2 receptor in Chinese hamster ovary cells resulted in an increase in basal cyclic AMP (cAMP) production, which was inhibited by the inverse agonists cimetidine, famotidine, and ranitidine with potencies similar to those found for the rat H2 receptor. Burimamide, a neutral antagonist at the rat H2 receptor, behaved as a weak partial agonist at the human H2 receptor. Burimamide competitively antagonized both the histamine-induced increase in cAMP and the cimetidine-induced reduction of the basal cAMP level with apparent KB values that were similar to its H2 receptor affinity. Investigation of the modulation of receptor expression after long-term drug treatment revealed that at low concentrations histamine induced a significant reduction in H2 receptor expression, whereas at high concentrations receptor expression was slightly increased. The partial agonist burimamide induced, like inverse agonists, an upregulation of the human H2 receptor after prolonged treatment. These findings suggest a structural instability of the constitutively active human H2 receptor in transfected Chinese hamster ovary cells. Occupation of the H2 receptor by any ligand reduces the instability, thus resulting in higher cellular expression levels.