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J. Biol. Chem., Vol. 277, Issue 35, 32099-32108, August 30, 2002

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Involvement of Both G_q/11 and G_s Proteins in Gonadotropin-releasing Hormone Receptor-mediated Signaling in LT2 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 LT2 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 G_i 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 G_q/11 and G_s proteins are involved in signaling. Consistent with this, GnRH caused GTP loading on G_s and G_q/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 G_q and G_s signaling to regulate gene expression in LT2 cells.

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