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Vol. 60, Issue 5, 1133-1142, November 2001
B: Roles for G
- and G
q/11-Subunits in
Constitutive and Agonist-Mediated Signaling
Leiden/Amsterdam Center for Drug Research, Department of
Pharmacochemistry, Vrije Universiteit Amsterdam, Amsterdam, The
Netherlands
Nuclear factor 
B (NF-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 H1 receptor, which is also an important
player in allergic and inflammatory conditions, activates NF-B in
both a constitutive and agonist-dependent manner. Moreover, the
observed constitutive NF-B 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-B 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 G
-proteins or
G
-heterodimers. Members of the Gq/11-family of
G-proteins are most effective in increasing H1
constitutive activity. Also, coexpression of G2 in
combination with either G1 or G2 results
in an increased constitutive activity of the H1 receptor,
whereas scavenging of G-subunits by coexpression of
Gt completely neutralizes the constitutive, but not the
agonist-induced, NF-B activity. Our data suggest that both
Gq/11- and G-subunits play a role in the
agonist-induced, H1 receptor-mediated NF-B activation,
but that constitutive NF-B activation by the H1 receptor is primarily mediated through G-subunits.
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