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Originally published In Press as doi:10.1074/jbc.M203639200 on June 5, 2002
J. Biol. Chem., Vol. 277, Issue 35, 32099-32108, August 30, 2002
Involvement of Both Gq/11 and Gs Proteins
in Gonadotropin-releasing Hormone Receptor-mediated Signaling in L T2
Cells*
Fujun
Liu ,
Isao
Usui ,
Lui Guojing
Evans§,
Darrell A.
Austin§,
Pamela L.
Mellon¶ ,
Jerrold M.
Olefsky , and
Nicholas J. G.
Webster § **
From the Departments of Medicine and
¶ Reproductive Medicine, and the UCSD Cancer Center,
University of California, San Diego, California 92093 and the
§ Medical Research Service and San Diego Veterans Healthcare
System, San Diego, California 92161
The hypothalamic hormone gonadotropin-releasing
hormone (GnRH) stimulates the synthesis and release of the pituitary
gonadotropins. GnRH acts through a plasma membrane receptor that is a
member of the G protein-coupled receptor (GPCR) family. These receptors interact with heterotrimeric G proteins to initiate downstream signaling. In this study, we have investigated which G proteins are
involved in GnRH receptor-mediated signaling in L T2 pituitary gonadotrope cells. We have shown previously that GnRH activates ERK and
induces the c-fos and LH genes in these cells. Signaling via the Gi subfamily of G proteins was excluded, as neither
ERK activation nor c-Fos and LH induction was impaired by treatment with pertussis toxin or a cell-permeable peptide that sequesters G -subunits. GnRH signaling was partially mimicked by adenoviral expression of a constitutively active mutant of G q
(Q209L) and was blocked by a cell-permeable peptide that uncouples
G q from GPCRs. Furthermore, chronic activation of
G q signaling induced a state of GnRH resistance. A
cell-permeable peptide that uncouples G s from receptors
was also able to inhibit ERK, c-Fos, and LH , indicating that both
Gq/11 and Gs proteins are involved in
signaling. Consistent with this, GnRH caused GTP loading on
Gs and Gq/11 and increased intracellular cAMP.
Artificial elevation of cAMP with forskolin activated ERK and caused a
partial induction of c-Fos. Finally, treatment of G q
(Q209L)-infected cells with forskolin enhanced the induction of c-Fos
showing that the two pathways are independent and additive. Taken
together, these results indicate that the GnRH receptor activates both
Gq and Gs signaling to regulate gene expression
in L T2 cells.
*
This work was supported by a U54 Center Grant HD-12303 from
the National Institutes of Health.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
**
To whom correspondence should be addressed: Dept. of Medicine 0673, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA
92093-0673. E-mail: nwebster@ucsd.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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Copyright © 2002 by the American Society for Biochemistry and Molecular Biology.
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