Involvement of histamine H₁ and H₂ receptor inverse agonists in receptor's crossregulation

Histamine [2-(4-Imidazolyl)-ethylamine] modulates different biological processes, through histamine H₁ and H₂ receptors, and their respective blockers are widely used in treating allergic and gastric acid-related disorders. Histamine H₁ and H₂ 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 H₁ and H₂ receptor inverse agonists and how histamine H₁ and H₂ receptor inverse agonists interfere with the other receptor's response to agonists. By desensitization assays we demonstrate that histamine H₁ and H₂ receptor inverse agonists induce a crossregulation between both receptors. In this sense, the histamine H₁ receptor inverse agonists desensitize the cAMP response to amthamine, a histamine H₂ receptor agonist. In turn, histamine H₂ receptor inverse agonists interfere with histamine H₁ receptor signaling. We also determine that the crossdesensitization induced by histamine H₁ or H₂ receptor agonists alters the histamine inverse agonists receptor response: activation of histamine H₁ receptor affects cAMP response induced by histamine H₂ receptor inverse agonists, whereas histamine H₂ receptor agonist induces a negative regulation on the anti-inflammatory response of histamine H₁ receptor inverse agonists. Binding studies revealed that histamine H₁ and H₂ 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 H₁ and H₂ receptors that explain the effect of histamine H₁ and H₂ receptor inverse agonists and opens up new venues for novel therapeutic applications.