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Histamine (HA) is recognized by its target cells via four G-protein-coupled receptors, referred to as histamine H 1 -receptor (H 1 R), H 2 R, H 3 R, and H 4 R. Both H 1 R and H 4 R 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)H 1 R or mH 4 R at similar levels and analyzed HA-induced signalling in these cells. HA induced intracellular calcium mobilization  via  both mH 1 R and mH 4 R, with the mH 1 R being much more effective. Whereas cAMP accumulation was potentiated  via  the mH 1 R, it was reduced  via  the mH 4 R. The regulation of both second messengers  via  the H 4 R, but not the H 1 R, 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 H 4 R-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 mH 1 R- and mH 4 R-induced signalling, qualitative and quantitative differences on the levels of second messenger generation and also in terms of p38 MAPK function became evident.

Distinct Signalling Pathways of Murine Histamine H1- and H4-Receptors Expressed at Comparable Levels in HEK293 Cells