Involvement of histamine H and H receptor inverse agonists in receptor's crossregulation.

Histamine [2-(4-Imidazolyl)-ethylamine] modulates different biological processes, through histamine H and H receptors, and their respective blockers are widely used in treating allergic and gastric acid-related disorders. Histamine H and H receptor crossdesensitization and cointernalization induced by its agonists have been previously described. In this study, we show how this crosstalk determines the response to histamine H and H receptor inverse agonists and how histamine H and H receptor inverse agonists interfere with the other receptor's response to agonists. By desensitization assays we demonstrate that histamine H and H receptor inverse agonists induce a crossregulation between both receptors. In this sense, the histamine H receptor inverse agonists desensitize the cAMP response to amthamine, a histamine H receptor agonist. In turn, histamine H receptor inverse agonists interfere with histamine H receptor signaling. We also determine that the crossdesensitization induced by histamine H or H receptor agonists alters the histamine inverse agonists receptor response: activation of histamine H receptor affects cAMP response induced by histamine H receptor inverse agonists, whereas histamine H receptor agonist induces a negative regulation on the anti-inflammatory response of histamine H receptor inverse agonists. Binding studies revealed that histamine H and H receptors cointernalize after stimulus with histamine receptor inverse agonists. In addition, the inhibition of the internalization process prevents receptor crossregulation. Our study provides new insights in the mechanisms of action of histamine H and H receptors that explain the effect of histamine H and H receptor inverse agonists and opens up new venues for novel therapeutic applications.