Distinct Signalling Pathways of Murine Histamine H(1)- and H(4)-Receptors Expressed at Comparable Levels in HEK293 Cells

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.