Gonadotropin-releasing Hormone Receptor Initiates Multiple Signaling Pathways by Exclusively Coupling to Gq/11Proteins

Grosse, Robert; Schmid, Andrea; Schöneberg, Torsten; Herrlich, Andreas; Muhn, Peter; Schultz, Günter; Gudermann, Thomas

doi:10.1074/jbc.275.13.9193

Cited by 147 publications

(74 citation statements)

References 56 publications

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“…A Constitutively Active G␣ q Mutant Induces c-Fos and LH␤ Protein Expression Acutely in L␤T2 Cells-Previous studies have implicated the G q/11 proteins in GnRH signaling (18,19). To explore further the functional importance of G␣ q in GnRH induced-ERK activation, c-Fos and LH␤ protein expression in L␤T2 cells, we used recombinant adenovirus vectors expressing either wild-type (WT) or a constitutively active mutant (Q209L) G␣ q , or a control virus expressing ␤-galactosidase.…”

Section: Fig 1 Effect Of Ptx On Gnrh-induced Erk Activation and C-fmentioning

confidence: 99%

“…Similarly, in CHO-K1 and COS-7 cells expressing the human GnRH receptor, GnRH couples exclusively to the G q/11 family of G proteins (19). However, the GnRH receptor also couples to G s in primary pituitary cultures and G-GH3 cells.…”

mentioning

confidence: 99%

“…Studies using immuno-depletion and G protein labeling showed that the GnRH receptor is coupled to G q/11 in ␣T3-1 pituitary cells (18,19). Similarly, in CHO-K1 and COS-7 cells expressing the human GnRH receptor, GnRH couples exclusively to the G q/11 family of G proteins (19).…”

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confidence: 99%

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Involvement of Both Gq/11 and Gs Proteins in Gonadotropin-releasing Hormone Receptor-mediated Signaling in LβT2 Cells

Liu¹,

Usui²,

Evans³

et al. 2002

Journal of Biological Chemistry

174

125

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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 receptormediated 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 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 L␤T2 cells.The family of G protein-coupled receptors is the largest and most complex group of integral membrane proteins involved in signal transduction. These receptors can be activated by a diverse array of external stimuli, including growth factors, neurotransmitters, peptide, and protein hormones, chemokines, and other ligands. Agonist binding to a specific receptor on the cell surface causes a conformational change in the receptor that allows it to interact with its cognate G protein, stimulating guanine nucleotide exchange on the ␣-subunit of the G protein. The release of the GTP-bound ␣-subunit and ␤␥-subunits from the receptor-G protein complex initiates a broad range of intracellular signaling events, including the activation of classical effectors such as phospholipase C, adenylate cyclases, and ion channels, and regulation of the intracellular level of inositol phosphates, calcium, cyclic AMP, and other second messengers (for reviews see Refs. 1-8).Gonadotropin-releasing hormone (GnRH) 1 is a hypothalamic decapeptide, which serves as a key regulator of the reproductive system. In the pituitary, GnRH signals are transmitted via a specific cell surface receptor, which is a member of the G protein-coupled receptor superfamily. When GnRH binds to its receptor, it induces interaction of the receptor with heterot...

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Section: Fig 1 Effect Of Ptx On Gnrh-induced Erk Activation and C-fmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Involvement of Both Gq/11 and Gs Proteins in Gonadotropin-releasing Hormone Receptor-mediated Signaling in LβT2 Cells

Liu¹,

Usui²,

Evans³

et al. 2002

Journal of Biological Chemistry

174

125

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“…Fos is known to transrepress the induction of many genes (21). Rgs2 is a GTPase-activating protein that down-regulates the activity of G␣ q (22), the major G-protein utilized by the GnRH receptor (23). The small G-protein gem (kir) has recently been reported to down-regulate L-type calcium channel function (24).…”

Section: Confirmation Of Gene Regulation By Real-time Pcr-mentioning

confidence: 99%

Gonadotropin-releasing Hormone Receptor-coupled Gene Network Organization

Wurmbach¹,

Yuen²,

Ebersole³

et al. 2001

Journal of Biological Chemistry

169

146

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An early gene cDNA microarray was developed to study genes that are regulated immediately following gonadotropin-releasing hormone (GnRH) receptor activation. 956 selected candidate genes were printed in triplicate, a t statistic-based regulation algorithm was used for data analysis, and the response to GnRH in a time course from 1 to 6 h was determined. Measurements were highly reproducible within arrays, between arrays, and between experiments. Accuracy and algorithm reliability were established by real-time polymerase chain reaction assays of 60 genes. Gene changes ranging from 1.3-to 31-fold on the microarray were confirmed by real-time polymerase chain reaction. Many of the genes were found to be highly regulated. The regulated genes identified were all elevated at 1 h of treatment and returned nearly or completely to baseline levels of expression by 3 h of treatment. This broad, robust, and transient transcriptional response to constant GnRH exposure includes modulators of signal transduction (e.g. Rgs2 and IB), cytoskeletal proteins (e.g. ␥-actin), and transcription factors (e.g. c-Fos, Egr1, and LRG21). The interplay of the activators, repressors, and feedback inhibitors identified embodies a combinatorial code to direct the activity of specific downstream secondary genes.

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“…The GnRHR has been previously shown to be coupled to multiple G proteins during agonist activation, including G q , G 11 , G s , G i , G 14 , G 15 [3,4,[6][7][8]25] although some laboratories have suggested that such regulation are all secondary to G q/11 coupling [9]. Such a schema would limit the amount of information that the receptor might convey, of course.…”

Section: Introductionmentioning

confidence: 97%

Multiple G proteins compete for binding with the human gonadotropin releasing hormone receptor

Knollman

Conn

2008

Archives of Biochemistry and Biophysics

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The GnRH receptor is coupled to G proteins of the families G q and G 11 . G q and G 11 . Coupling leads to intracellular signaling through the phospholipase C pathway. GnRHR coupling to other G proteins is controversial. This study provides evidence that G protein families G s , G i , G q and G 11 complete for binding with the GnRHR. We quantified interactions of over-expressed G proteins with GnRHR by a competitive binding approach, using measurements of second messengers, IP and cAMP. Transient co-transfection of HEK293 cells with human WT GnRHR and with stimulatory and inhibitory G proteins (G q , G 11 and G s , G i ) led to either production or inhibition of total inositol phosphate (IP) production, depending on the G protein that was over-expressed. Studies were conducted in different human (COS7, HeLa) and rodent-derived (CHO-K1, GH 3 ) cell lines in order to confirm that G-protein promiscuity observed with the GnRHR was not limited to a particular cell type.

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Gonadotropin-releasing Hormone Receptor Initiates Multiple Signaling Pathways by Exclusively Coupling to Gq/11Proteins

Cited by 147 publications

References 56 publications

Involvement of Both Gq/11 and Gs Proteins in Gonadotropin-releasing Hormone Receptor-mediated Signaling in LβT2 Cells

Involvement of Both Gq/11 and Gs Proteins in Gonadotropin-releasing Hormone Receptor-mediated Signaling in LβT2 Cells

Gonadotropin-releasing Hormone Receptor-coupled Gene Network Organization

Multiple G proteins compete for binding with the human gonadotropin releasing hormone receptor

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