CONSTITUTIVE ACTIVITY AND STRUCTURAL INSTABILITY OF THE WILD-TYPE HUMAN H-2-RECEPTOR

Stable expression of the human H-2 receptor in Chinese hamster ovary c ells resulted in an increase in basal cyclic AMP (cAMP) production, wh ich was inhibited by the inverse agonists cimetidine, famotidine, and ranitidine with potencies similar to those found for the rat H-2 recep tor. Burimamide, a neutral antagonist at the rat H-2 receptor, behaved as a weak partial agonist at the human H-2, receptor. Burimamide comp etitively antagonized both the histamine-induced increase in cAMP and the cimetidine-induced reduction of the basal cAMP level with apparent K-B values that were similar to its H-2 receptor affinity. Investigat ion of the modulation of receptor expression after long-term drug trea tment revealed that at low concentrations histamine induced a signific ant reduction in H-2 receptor expression, whereas at high concentratio ns receptor expression was slightly increased. The partial agonist bur imamide induced, like inverse agonists, an upregulation of the human H -2 receptor after prolonged treatment, These findings suggest a struct ural instability of the constitutively active human H-2 receptor in tr ansfected Chinese hamster ovary cells. Occupation of the H-2 receptor by any ligand reduces the instability, thus resulting in higher cellul ar expression levels.