Effects of histamine H1 receptor signaling on glucocorticoid receptor activity. Role of canonical and non-canonical pathways

ZAPPIA C D; GRANJA GALEANO G; FERNANDEZ NATALIA; SHAYO C; DAVIO C; FITZSIMONS C; MONCZOR F

Scientific Reports

Nature Publishing Group

Año: 2015

Histamine H1 receptor (H1R) antagonists and glucocorticoid receptor (GR) agonists are used to treatinflammatory conditions such as allergic rhinitis, atopic dermatitis and asthma. Consistent with thehigh morbidity levels of such inflammatory conditions, these receptors are the targets of a vastnumber of approved drugs, and in many situations their ligands are co-administered. However, thisdrug association has no clear rationale and has arisen from clinical practice. We hypothesized thatH1R signaling could affect GR-mediated activity, impacting on its transcriptional outcome. Indeed,our results show a dual regulation of GR activity by the H1R: a potentiation mediated by G-proteinβγ subunits and a parallel inhibitory effect mediated by Gαq-PLC pathway. Activation of the H1R byits full agonists resulted in a composite potentiating effect. Intriguingly, inactivation of the Gαq-PLCpathway by H1R inverse agonists resulted also in a potentiation of GR activity. Moreover, histamineand clinically relevant antihistamines synergized with the GR agonist dexamethasone to inducegene transactivation and transrepression in a gene-specific manner. Our work provides a delineationof molecular mechanisms underlying the widespread clinical association of antihistamines and GRagonists, which may contribute to future dosage optimization and reduction of well-described sideeffects associated with glucocorticoid administration.