Biased agonism at histamine H₁ receptor: Desensitization, internalization and MAPK activation triggered by...

Histamine H₁ 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 (IP₃)-Ca²⁺ 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 H₁ 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 H₁ receptor mediated Ca²⁺ response, and both diphenhydramine and triprolidine lead to receptor internalization. Unlike histamine, histamine H₁ 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 H₁ 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 H₁ receptor ligands contributing to a more accurate classification, and providing evidence for a more rational and safe use of them.