Biased agonism at histamine H1 receptor: Desensitization, internalization and MAPK activation triggered by antihistamines
| Autor: | Carina Shayo, Antonela Díaz Nebreda, Natalia Gómez, Federico Monczor, Natalia Cristina Fernandez, Carlos Daniel Zappia, Sonia Ripoll, Valeria Burghi, Emiliana Beatriz Echeverría, Carlos Davio |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Pharmacology Agonist biology medicine.drug_class Chemistry media_common.quotation_subject Beta adrenergic receptor kinase Histamine H1 receptor 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine medicine biology.protein Functional selectivity Internalization Triprolidine 030217 neurology & neurosurgery Histamine medicine.drug media_common G protein-coupled receptor |
| Zdroj: | European Journal of Pharmacology. 896:173913 |
| ISSN: | 0014-2999 |
| DOI: | 10.1016/j.ejphar.2021.173913 |
| Popis: | 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 Gαq-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 Gαq 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. |
| Databáze: | OpenAIRE |
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