Histamine H 1 -Receptor Activation of Nuclear Factor- κ B: Roles for Gβγ- and Gα q/11 -Subunits in Constitutive and Agonist-Mediated Signaling

Nuclear factor κ B (NF- κ B) 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- κ B in both a constitutive and agonist-dependent manner. Moreover, the observed constitutive NF- κ B 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- κ B 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 Gα-proteins or Gβγ-heterodimers. Members of the Gα q/11 -family of Gα-proteins are most effective in increasing H 1 constitutive activity. Also, coexpression of Gβ 2 in combination with either Gγ 1 or Gγ 2 results in an increased constitutive activity of the H 1 receptor, whereas scavenging of Gβγ-subunits by coexpression of Gα t completely neutralizes the constitutive, but not the agonist-induced, NF- κ B activity. Our data suggest that both Gα q/11 - and Gβγ-subunits play a role in the agonist-induced, H 1 receptor-mediated NF- κ B activation, but that constitutive NF- κ B activation by the H 1 receptor is primarily mediated through Gβγ-subunits.