title: Effects of histamine H1 receptor signaling on glucocorticoid receptor activity. Role of canonical and non-canonical pathways.
abstract: Histamine H1 receptor (H1R) antagonists and glucocorticoid receptor (GR) agonists are used to treat inflammatory conditions such as allergic rhinitis, atopic dermatitis and asthma. Consistent with the high morbidity levels of such inflammatory conditions, these receptors are the targets of a vast number of approved drugs, and in many situations their ligands are co-administered. However, this drug association has no clear rationale and has arisen from clinical practice. We hypothesized that H1R 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-protein βγ subunits and a parallel inhibitory effect mediated by Gαq-PLC pathway. Activation of the H1R by its full agonists resulted in a composite potentiating effect. Intriguingly, inactivation of the Gαq-PLC pathway by H1R inverse agonists resulted also in a potentiation of GR activity. Moreover, histamine and clinically relevant antihistamines synergized with the GR agonist dexamethasone to induce gene transactivation and transrepression in a gene-specific manner. Our work provides a delineation of molecular mechanisms underlying the widespread clinical association of antihistamines and GR agonists, which may contribute to future dosage optimization and reduction of well-described side effects associated with glucocorticoid administration.
authors.affiliation: Laboratorio de Farmacología de Receptores, Cátedra de Química Medicinal, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires. Buenos Aires, Argentina.|Instituto de Investigaciones Farmacológicas, ININFA. Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET. Buenos Aires, Argentina.
authors.forename: Carlos Daniel
authors.initials: CD
authors.lastname: Zappia
authors.affiliation: Laboratorio de Farmacología de Receptores, Cátedra de Química Medicinal, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires. Buenos Aires, Argentina.|Instituto de Investigaciones Farmacológicas, ININFA. Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET. Buenos Aires, Argentina.
authors.forename: Gina
authors.initials: G
authors.lastname: Granja-Galeano
authors.affiliation: Laboratorio de Farmacología de Receptores, Cátedra de Química Medicinal, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires. Buenos Aires, Argentina.|Instituto de Investigaciones Farmacológicas, ININFA. Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET. Buenos Aires, Argentina.
authors.forename: Natalia
authors.initials: N
authors.lastname: Fernández
authors.affiliation: Laboratorio de Patología y Farmacología Molecular, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina.
authors.forename: Carina
authors.initials: C
authors.lastname: Shayo
authors.affiliation: Laboratorio de Farmacología de Receptores, Cátedra de Química Medicinal, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires. Buenos Aires, Argentina.|Instituto de Investigaciones Farmacológicas, ININFA. Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET. Buenos Aires, Argentina.
authors.forename: Carlos
authors.initials: C
authors.lastname: Davio
authors.affiliation: Neuroscience Programme, Swammerdam Institute for Life Sciences, University of Amsterdam, SciencePark 904, 1098XH Amsterdam, The Netherlands.
authors.forename: Carlos P
authors.initials: CP
authors.lastname: Fitzsimons
authors.affiliation: Laboratorio de Farmacología de Receptores, Cátedra de Química Medicinal, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires. Buenos Aires, Argentina.|Instituto de Investigaciones Farmacológicas, ININFA. Universidad de Buenos Aires-Consejo Nacional de Investigaciones Científicas y Técnicas, CONICET. Buenos Aires, Argentina.
authors.forename: Federico
authors.initials: F
authors.lastname: Monczor
mesh_terms: D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003345:Corticosterone / Q000008:administration & dosage; D003876:Dermatitis, Atopic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003907:Dexamethasone / Q000008:administration & dosage; D006367:HeLa Cells; D006632:Histamine / Q000378:metabolism; D017442:Histamine Agonists / Q000008:administration & dosage / Q000378:metabolism; D006634:Histamine H1 Antagonists / Q000378:metabolism; D006801:Humans; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D017442:Histamine Agonists; D006634:Histamine H1 Antagonists; D011965:Receptors, Glucocorticoid; D011969:Receptors, Histamine H1; D003907:Dexamethasone; D006632:Histamine; D003345:Corticosterone