Biased agonism at histamine H1 receptors

ANTONELA DIAZ-NEBREDA; CARLOS DAVIO; VALERIA BURGHI; DANIEL ZAPPIA; FEDERICO MONCZOR; EMILIANA ECHEVERRÍA; CARINA SHAYO; NATALIA FERNANDEZ

Mar del Plata

Congreso; LXIII Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica; 2018

Sociedad Argentina de Investigación Clínica

GPCRs (G-protein coupled receptors) exist as conformational collections in which differentconformations lead to differential downstream behaviors such as G-protein activation,receptor phosphorylation or internalization. In this context, a ligand may cause differentialactivation of some, but not all, of the signaling events associated to a particular receptorand would lead to biased agonism. On the other hand, antihistamines used clinically asantiallergics rank among the most widely prescribed and over-the-counter drugs in theworld. The aim of the present study was to investigate whether widely used histamine H1receptor (H1R) ligands that exert therapeutic actions by blocking the effects of histamine,due to null or negative efficacy towards Gα q -phospholipase C (PLC)-inositol triphosphates(IP3) and Nuclear Factor-kB cascades, could display positive efficacy concerning receptordesensitization or internalization. We used A549 cells, derived from human lungepithelium, endogenously expressing the H1R. Pretreatment of A549 cells during 10minutes with 1, 3, 10 and 33 μM of chlorpheniramine and triprolidine prevented theincrease of cytosolic Ca 2+ levels evoked by 100 μM of histamine suggesting that bothligands may promote H1R desensitization. On the contrary, pretreatment withdiphenhydramine did not modify the H1R response to the agonist. To examine themechanisms involved in these desensitizations we transfected A549 cells with GRK2 anddynamin dominant-negative mutants. Our results indicate that although these mutantspotentiate calcium response to histamine and partially impaired histamine induced H1Rdesensitization they did not revert chlorpheniramine nor triprolidine induceddesensitization. Finally, preliminary results of saturation-binding assays suggest that someof these ligands may also lead to receptor internalization. In conclusion, H1Rdesensitization and/or internalization promoted by these ligands demonstrate their biasednature and could explain their undesired effects. Accordingly, this study contributes to acorrect classification, providing evidence for a more rational and safe use of antihistamines.