Histamine H1-receptor activation of nuclear factor-κB:: Roles for Gβγ- and Gαq/11-subunits in constitutive and agonist-mediated signaling

Nuclear factor KB (NF-kappaB) is an important transcription factor in inflammation that has obtained a great interest as a drug target for the treatment of various allergic conditions. In this study, we show that the histamine H-1 receptor, which is also an important player in allergic and inflammatory conditions, activates NF-kappaB in both a constitutive and agonist-dependent manner. Moreover, the observed constitutive NF-kappaB activation is inhibited by various H-1-receptor antagonists, suggesting that inverse agonism may account, at least in part, for their ascribed antiallergic properties. Investigation of the H-1 receptor-mediated NF-kappaB activation in transfected COS-7 cells indicates that the level of the observed constitutive activity of the H-1 receptor can be modulated by the expression levels of, either Ga-proteins or G beta gamma -heterodimers. Members of the G alpha (q/11)-family of Ga-proteins are most effective in increasing H-1 constitutive activity. Also, coexpression of G beta (2) in combination with either G gamma (1) or G-gamma (2) results in an increased constitutive activity of the H-1 receptor, whereas scavenging of G beta gamma -subunits by coexpression of Gat completely neutralizes the constitutive, but not the agonist-induced, NF-kappaB activity. Our data suggest that both G alpha (q/11)- and G beta gamma -subunits play a role in the agonist-induced, H-1 receptor-mediated NF-kappaB activation, but that constitutive NF-KB activation by the H-1 receptor is primarily mediated through G beta gamma -subunits.