title: Distinct signalling pathways of murine histamine H1- and H4-receptors expressed at comparable levels in HEK293 cells.
abstract: Histamine (HA) is recognized by its target cells via four G-protein-coupled receptors, referred to as histamine H1-receptor (H1R), H2R, H3R, and H4R. Both H1R and H4R exert pro-inflammatory functions. However, their signal transduction pathways have never been analyzed in a directly comparable manner side by side. Moreover, the analysis of pharmacological properties of the murine orthologs, representing the main targets of pre-clinical research, is very important. Therefore, we engineered recombinant HEK293 cells expressing either mouse (m)H1R or mH4R at similar levels and analyzed HA-induced signalling in these cells. HA induced intracellular calcium mobilization via both mH1R and mH4R, with the mH1R being much more effective. Whereas cAMP accumulation was potentiated via the mH1R, it was reduced via the mH4R. The regulation of both second messengers via the H4R, but not the H1R, was sensitive to pertussis toxin (PTX). The mitogen-activated protein kinases (MAPKs) ERK 1/2 were massively activated downstream of both receptors and demonstrated a functional involvement in HA-induced EGR-1 gene expression. The p38 MAPK was moderately activated via both receptors as well, but was functionally involved in HA-induced EGR-1 gene expression only in H4R-expressing cells. Surprisingly, in this system p38 MAPK activity reduced the HA-induced gene expression. In summary, using this system which allows a direct comparison of mH1R- and mH4R-induced signalling, qualitative and quantitative differences on the levels of second messenger generation and also in terms of p38 MAPK function became evident.
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Hannover, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Beermann
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Hannover, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Vauth
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Hannover, Germany.
authors.forename: Rabea
authors.initials: R
authors.lastname: Hein
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Hannover, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Seifert
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Hannover, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Neumann
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011968:Receptors, Histamine / Q000378:metabolism*; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D000074040:Receptors, Histamine H4; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C418607:HRH4 protein, human; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D011969:Receptors, Histamine H1; D000074040:Receptors, Histamine H4; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium