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Constitutive Activity and Structural Instability of the Wild‐Type Human H 2 Receptor
Author(s) -
Alewijnse Astrid E.,
Smit Martine J.,
Hoffmann Marcel,
Verzijl Dennis,
Timmerman Henk,
Leurs Rob
Publication year - 1998
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1998.71020799.x
Subject(s) - inverse agonist , endocrinology , receptor , medicine , chinese hamster ovary cell , agonist , enzyme linked receptor , receptor expression , partial agonist , interleukin 21 receptor , homologous desensitization , receptor antagonist , chemistry , biology , antagonist
Stable expression of the human H 2 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 H 2 receptor. Burimamide, a neutral antagonist at the rat H 2 receptor, behaved as a weak partial agonist at the human H 2 receptor. Burimamide competitively 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. Investigation of the modulation of receptor expression after long‐term drug treatment revealed that at low concentrations histamine induced a significant reduction in H 2 receptor expression, whereas at high concentrations receptor expression was slightly increased. The partial agonist burimamide induced, like inverse agonists, an upregulation of the human H 2 receptor after prolonged treatment. These findings suggest a structural instability of the constitutively active human H 2 receptor in transfected Chinese hamster ovary cells. Occupation of the H 2 receptor by any ligand reduces the instability, thus resulting in higher cellular expression levels.