Histamine H1-Receptor Activation of Nuclear Factor-κB: Roles for Gβγ- and Gαq/11-Subunits in Constitutive and Agonist-Mediated Signaling

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Abstract
Nuclear factor κB (NF-κB) 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 H1 receptor, which is also an important player in allergic and inflammatory conditions, activates NF-κB in both a constitutive and agonist-dependent manner. Moreover, the observed constitutive NF-κB activation is inhibited by various H1-receptor antagonists, suggesting that inverse agonism may account, at least in part, for their ascribed antiallergic properties. Investigation of the H1 receptor-mediated NF-κB activation in transfected COS-7 cells indicates that the level of the observed constitutive activity of the H1 receptor can be modulated by the expression levels of either Gα-proteins or Gβγ-heterodimers. Members of the Gαq/11-family of Gα-proteins are most effective in increasing H1constitutive activity. Also, coexpression of Gβ2 in combination with either Gγ1 or Gγ2 results in an increased constitutive activity of the H1 receptor, whereas scavenging of Gβγ-subunits by coexpression of Gαt completely neutralizes the constitutive, but not the agonist-induced, NF-κB activity. Our data suggest that both Gαq/11- and Gβγ-subunits play a role in the agonist-induced, H1 receptor-mediated NF-κB activation, but that constitutive NF-κB activation by the H1 receptor is primarily mediated through Gβγ-subunits.