title: Histamine H(1)- and H(4)-receptor signaling cooperatively regulate MAPK activation.
abstract: The histamine (HA) receptor subtype 1 (H1R) and H4R are expressed on immune cells and contribute to an inflammatory reaction. Both receptor subtypes individually enhance the intracellular concentrations of calcium and regulate the accumulation of cAMP, increase MAPK activity, and regulate expression of e.g., inflammatory genes. In a previous study we characterized and compared signaling pathways of the murine orthologs of the H1R and the H4R recombinantly expressed at comparable levels in HEK 293 cells. In the present study, we aimed at analyzing possible interactions of the signaling pathways emerging at the mH1R and the mH4R. Therefore, we co-expressed both receptor subtypes at comparable levels in HEK 293 cells and investigated HA-induced signaling parameters such as the concentrations of intracellular calcium and cAMP, phosphorylation of the MAPKs p38, ERK 1, and ERK 2, and of the transcription factor CREB, and expression of the immediate early gene EGR-1. We demonstrate that the intracellular concentrations of calcium and cAMP as well as the EGR-1 expression are regulated exclusively via the mH1R. In contrast, both receptor subtypes H1R and H4R synergize in HA-induced MAPK activation. This synergism most probably relies on signaling pathways independent of the second messenger calcium and cAMP. In summary, we provide evidence that the mH1R inhibits or dampens the function of the co-expressed mH4R regarding specific parameters, while other signaling events are regulated cooperatively by the mH1R and the mH4R.
authors.affiliation: Hannover Medical School, Institute of Pharmacology, Hannover, Germany. Electronic address: silke.beermann@radboudumc.nl.
authors.forename: Silke
authors.initials: S
authors.lastname: Beermann
authors.affiliation: University of Regensburg, Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry II, Regensburg, Germany. Electronic address: guenther.bernhardt@chemie.uni-regensburg.de.
authors.forename: Guenther
authors.initials: G
authors.lastname: Bernhardt
authors.affiliation: Hannover Medical School, Institute of Pharmacology, Hannover, Germany. Electronic address: seifert.roland@mh-hanover.de.
authors.forename: Roland
authors.initials: R
authors.lastname: Seifert
authors.affiliation: University of Regensburg, Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry II, Regensburg, Germany. Electronic address: armin.buschauer@chemie.uni-regensburg.de.
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
authors.affiliation: Hannover Medical School, Institute of Pharmacology, Hannover, Germany. Electronic address: neumann.detlef@mh-hannover.de.
authors.forename: Detlef
authors.initials: D
authors.lastname: Neumann
mesh_terms: D002118:Calcium / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; 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
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
keywords: G protein-coupled receptor; Histamine receptor; Inflammation; Mitogen-activated protein kinase; Second messenger