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Histamine H 1 receptor ligands used clinically as antiallergics rank among the most widely prescribed and over-the-counter drugs in the world. They exert the therapeutic actions by blocking the effects of histamine, due to null or negative efficacy towards Gα q -phospholipase C (PLC)-inositol triphosphates (IP 3 )-Ca 2+ and nuclear factor-kappa B cascades. However, there is no information regarding their ability to modulate other receptor responses. The aim of the present study was to investigate whether histamine H 1 receptor ligands could display positive efficacy concerning receptor desensitization, internalization, signaling through Gα q independent pathways or even transcriptional regulation of proinflammatory genes. While diphenhydramine, triprolidine and chlorpheniramine activate ERK1/2 (extracellular signal-regulated kinase 1/2) pathway in A549 cells, pre-treatment with chlorpheniramine or triprolidine completely desensitize histamine H 1 receptor mediated Ca 2+ response, and both diphenhydramine and triprolidine lead to receptor internalization. Unlike histamine, histamine H 1 receptor desensitization and internalization induced by antihistamines prove to be independent of G protein-coupled receptor kinase 2 (GRK2) phosphorylation. Also, unlike the reference agonist, the recovery of the number of cell-surface histamine H 1 receptors is a consequence of de novo synthesis. On the other hand, all of the ligands lack efficacy regarding cyclooxygenase-2 (COX-2) and interleukin-8 (IL-8) mRNA regulation. However, a prolonged exposure with each of the antihistamines impaires the increase in COX-2 and IL-8 mRNA levels induced by histamine, even after ligand removal. Altogether, these findings demonstrate the biased nature of histamine H 1 receptor ligands contributing to a more accurate classification, and providing evidence for a more rational and safe use of them., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Histamine [2-(4-Imidazolyl)-ethylamine] modulates different biological processes, through histamine H 1 and H 2 receptors, and their respective blockers are widely used in treating allergic and gastric acid-related disorders. Histamine H 1 and H 2 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 1 and H 2 receptor inverse agonists and how histamine H 1 and H 2 receptor inverse agonists interfere with the other receptor's response to agonists. By desensitization assays we demonstrate that histamine H 1 and H 2 receptor inverse agonists induce a crossregulation between both receptors. In this sense, the histamine H 1 receptor inverse agonists desensitize the cAMP response to amthamine, a histamine H 2 receptor agonist. In turn, histamine H 2 receptor inverse agonists interfere with histamine H 1 receptor signaling. We also determine that the crossdesensitization induced by histamine H 1 or H 2 receptor agonists alters the histamine inverse agonists receptor response: activation of histamine H 1 receptor affects cAMP response induced by histamine H 2 receptor inverse agonists, whereas histamine H 2 receptor agonist induces a negative regulation on the anti-inflammatory response of histamine H 1 receptor inverse agonists. Binding studies revealed that histamine H 1 and H 2 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 1 and H 2 receptors that explain the effect of histamine H 1 and H 2 receptor inverse agonists and opens up new venues for novel therapeutic applications., (Copyright © 2019 Elsevier B.V. All rights reserved.)