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Differential Gonadotropin-Releasing Hormone Stimulation of Rat Luteinizing Hormone Subunit Gene Transcription by Calcium Influx and Mitogen-Activated Protein Kinase-Signaling Pathways

Department of Molecular Physiology and Biological Physics (J.W., M.A.S.) Department of Medicine Division of Endocrinology and The National Science Foundation Center for Biological Timing (P.C.F., L.K.P., M.A.S.) University of Virginia, Charlottesville, Virginia 22908

	ABSTRACT

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Gonadotropin secretion and gene expression are differentially regulated by hypothalamic GnRH pulses by unknown mechanisms. GnRH stimulates calcium influx through L-type voltage-gated channels and activates phospholipase C, leading to increased protein kinase C (PKC) and mitogen-activated protein kinase activity. We found differential contributions of these pathways to GnRH-stimulated rat LH subunit transcription in pituitary gonadotropes and cell lines. Endogenous transcription of the - and LHß-subunits in rat pituitary cells was stimulated by GnRH. Independent PKC activation by phorbol myristate acid stimulated only the -subunit gene. In contrast, an L-channel antagonist (nimodipine) inhibited only LHß stimulation by GnRH, and an L-channel agonist (BayK 8644) stimulated only basal LHß transcription. GnRH induction of a rat -subunit promoter construct in T3 cells was unaffected by nimodipine or elimination of external calcium, while both treatments eliminated the LHß response. Application of a mitogen-activated kinase kinase (MEK) inhibitor (PD098059) decreased basal and GnRH-stimulated -subunit promoter activity and had no effect on LHß promoter activity. In pituitary cells from mice bearing an LHß promoter-luciferase reporter transgene, GnRH stimulation was inhibited by nimodipine but not by PD098059. Thus, GnRH induction and basal control of the -subunit gene seem to occur through the PKC/mitogen-activated protein kinase pathway, while induction of the LHß gene is dependent on calcium influx. Differential signaling from the same receptor may be a mechanism for preferential regulation of transcription.

	INTRODUCTION

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The hypothalamic peptide GnRH is released into pituitary portal vessels in intermittent pulses, the frequency and amplitude of which vary physiologically (1, 2, 3, 4). Pulsatile GnRH release is necessary for reproductive function, as continuous infusion of the peptide results in infertility. GnRH acts on anterior pituitary gonadotropes to stimulate production and secretion of the gonadotropins LH and FSH. These proteins are composed of two noncovalently linked subunits, the (common to TSH, FSH, and LH) and a ß-subunit specific to each protein. Each ß-subunit as well as the common is encoded by different genes on separate chromosomes. LH stimulates gametogenesis and gonadal steroid production necessary for fertility. Transcriptional activation of gonadotropin subunit genes is differentially regulated by GnRH pulse frequency in vivo and in vitro (5, 6). Transcription from the rat -subunit gene is stimulated by pulses of intermediate or short intervals, or by constant GnRH, whereas activation of the rat LHß gene occurs only with intermediate-frequency (30 min), high-amplitude pulses. Given this differential regulation, some mechanistic differences must exist.

The mechanisms by which GnRH causes such differential control within gonadotropes are unknown but may include activation of different transcription factors for each gene or preferential sensitivity to distinct second messenger pathways. These mechanisms are not mutually exclusive. Transfection experiments in cultured pituitary cells and cell lines and studies involving transgenic mice have identified several cis-acting elements responsible for expression of the human, bovine, and mouse -subunit promoters (7, 8, 9, 10, 11). Less is known about LHß promoter regulation. However, transfection studies in primary cultures, heterologous cell lines, and transgenic mice expressing either rat or bovine LHß reporters illustrate activation of both LHß transgene and endogenous gene expression by GnRH, and this activation is attenuated in vivo by increased steroid levels or by a GnRH antagonist (12, 13, 14, 15, 16). GnRH stimulation of gonadotropes activates two primary signaling pathways, calcium and protein kinase C (PKC) (17, 18, 19, 20). Receptor activation induces a biphasic increase in internal calcium, with an initial spike dependent on internal calcium stores, and a sustained plateau that is dependent on increased Ca⁺⁺ influx through L-type channels (21, 22). GnRH binding also activates G proteins (G_q and G₁₁) that stimulate phospholipase C ß activity to generate inositol triphosphate and diacylgycerol. Activation of this pathway results in PKC and thus mitogen-activated protein kinase (MAPK) stimulation (23, 24, 25, 26, 27).

We sought to determine the mechanisms by which the rat and LHß genes are regulated by GnRH. In the current study we examined rat LH subunit promoter expression in normal pituitaries, transfected cell lines, and pituitaries from mice bearing a rat LHß- promoter-luciferase transgene. By manipulating the two major pathways activated in response to GnRH, the influx of Ca⁺⁺ and the activation of MAPK via PKC, we illustrate stimulation of MAPK activates the rat -subunit gene preferentially, while Ca⁺⁺ influx is more important in activating the LHß gene.

	RESULTS

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Transcriptional Analysis of the Endogenous Genes
Transcription rates of endogenous rat and LHß genes were measured by nuclear run-off assays in isolated rat pituitary cells treated with GnRH and various pharmacological agents (Fig. 1). Both genes were stimulated by GnRH (, 5-fold, and LHß, 9-fold) but differ in their sensitivity to modulators of GnRH-signaling pathways. To determine the contribution of GnRH-stimulated increase in calcium influx through L-channels, Bay K8644, a specific L-channel agonist, and nimodipine, an L-channel antagonist, were used. Bay K only slightly increased gene mRNA synthesis (1.5-fold) but stimulated LHß gene transcription by 7- to 9-fold, equal to the stimulation seen with GnRH. Nimodipine decreased GnRH stimulation of the gene only partially, but had a marked effect on the LHß response, decreasing GnRH-mediated stimulation from 9- to 3-fold. The effects of PKC activation were assessed by stimulating the pathway with the phorbol ester phorbol myristate acid (PMA). PMA stimulated -subunit mRNA synthesis 4-fold, but did not significantly increase transcription of the LHß gene. Therefore, although GnRH stimulation of pituitary gonadotropes activates both the Ca⁺⁺- and PKC-regulated second messenger systems, these pathways do not affect rat -subunit and LHß gene transcription identically. The -subunit gene is much more susceptible to stimulation by the PKC pathway, and increases in Ca⁺⁺ influx preferentially stimulate LHß gene transcription.

View larger version (21K): [in this window] [in a new window]   Figure 1. Transcription Rates of Endogenous LH Subunit Genes in Isolated Rat Pituitaries mRNA synthesis from endogenous and LHß genes was measured in response to different treatments. Dispersed pituitary cells were treated for 30 min with GnRH (10 nM), the PKC activator PMA (100 nM), the L-type calcium channel agonist BayK8644 (BayK, 50 nM), or the L-type calcium channel antagonist nimodipine (100 nM). Nuclei were then isolated and transcription rates measured. Values are expressed in parts per million (ppm) and represent mean ± SEM for three or four samples per group. * indicates P < 0.05 and ** P < 0.01 vs. control.

In T3 cells, GnRH stimulated both LUC and LHßtkLUC reporter activity (Fig. 2). Chelation of external calcium with EGTA did not alter the LUC response to GnRH. However, the same amount of EGTA in the media decreased GnRH stimulation of LHßtkLUC to basal levels. EGTA alone had no effect on either construct. GnRH stimulation of LUC was slightly decreased with nimodipine, the specific L-channel antagonist (Fig. 2). In contrast, application of nimodipine eliminated GnRH activation of LHßtkLUC, indicating that calcium influx through L-type voltage-gated channels is necessary for GnRH stimulation of the LHß promoter region.

View larger version (29K): [in this window] [in a new window]   Figure 2. Effect of GnRH-induced Calcium Influx on LH Subunit Reporters in T3 Cells T3 cells were transfected with either LUC or LHßtkLUC for 16 h and then treated for 6 h with EGTA (2 mM) or nimodipine (Nimo 100 nM) in the presence or absence of GnRH (10 nM). Normalized values relative to untreated controls are shown and represent the average of four to eight experiments. ** indicates P < 0.01 and *** indicates P < 0.001 as compared with paired controls.

View larger version (25K): [in this window] [in a new window]   Figure 3. Effect of MEK Inhibitor on LH Subunit Reporters in T3 Cells T3 cells were transfected with either LUC or LHßtkLUC for 16 h and then treated with the MEK inhibitor PD098059 (50 µM) in the presence or absence of GnRH. Normalized values relative to untreated controls are shown and represent the average of four to eight experiments. *** indicates P < 0.001 as compared with basal levels. a indicates P < 0.05 as compared with PD treatment.

View larger version (33K): [in this window] [in a new window]   Figure 4. LHß Promoter Stimulation in Transgenic Mice Isolated pituitary cells from male transgenic mice bearing the LHß-luciferase transgene were treated for 4 h with GnRH (10 nM), PD098059 (50 µM), or nimodipine (100 nM). *, P < 0.05 vs. control for six samples per group.

	DISCUSSION

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The requirement for MAPK activation for GnRH stimulation of the rat promoter agrees with data using the mouse and human -subunit promoters (25, 26). GnRH activation of the mouse -subunit promoter was attenuated by overexpression of a kinase-defective MAPK or overexpression of MAPK phosphatase 2 in T3 cells (25). The transcription factors binding the GnRH-responsive region of the mouse gene have not been described although one has been postulated to be an Ets family protein. Members of this family have been demonstrated to be phosphorylated and activated by MAPK (31, 32). The DNA-binding domains of two family members, Ets-2 and ER81, contact a GGAA sequence in the mouse GnRH response element, and cotransfection with a dominant negative Ets-2 reduces GnRH stimulation. Others demonstrated that both PKC depletion and cotransfection of dominant negative MAPK (ERK1 and ERK2) suppress basal and GnRH-stimulated human -subunit promoter activity (26, 27). The human and mouse -subunit genes contain an Ets domain protein-binding site in the GnRH-responsive regions, whereas the rat gene contains two, between bases -411 and -375.¹ Thus, all the -subunit genes contain potential sites for binding proteins directly activated by MAPK. Several studies illustrate the dependence of human -subunit promoter expression on both calcium influx and PKC activation in T3 cells (33, 34). In our experiments, GnRH-induced rat -subunit promoter activity was only slightly affected by nimodipine or by chelation of external calcium by EGTA, indicating that external calcium influx has less influence on the rat than the human -subunit promoter when studied in the same cell context. As promoter sequence homology between species ranges from 71–90%, some differences in DNA sequence within the GnRH-sensitive region or other promoter areas could account for observed variations in the transcriptional responses to calcium vs. MEK-stimulated pathways.

The differences in transcriptional responses of the rat LH subunit genes are reflected in promoter sequences (12, 41). No Ets family-binding sites were identified in the rat LHß GnRH-responsive region between -617 and -245, perhaps explaining the relative lack of sensitivity to the MEK/MAPK pathway. Steroidogenic factor-1 (SF-1) sites are found in the -subunit, GnRH receptor, and rat and bovine LHß subunit promoters and are critical for basal activity of these genes in vitro and in vivo (35, 36, 37). However, these SF-1 sites are not contained in the GnRH-responsive portion of the rat LHß reporter used in transfection studies. Others have also suggested that these SF-1 sites are not primarily responsible for GnRH stimulation of this gene (36). Our studies using transgenes, transfection constructs, and endogenous LHß gene activity show similar sensitivity to pharmacological agents and suggest that calcium influx plays a major role in GnRH stimulation of this gene. Calcium-sensitive activation is not regulated by a single transcription factor, and several types of transcription factor-binding sites and different transcription factors can contribute to stimulation by this pathway (38, 39). Cross-talk between signaling pathways has also been noted in gonadotropes and other cell types; therefore, cooperation between PKC stimulation and calcium influx may also occur, and this could result in LHß stimulation (17, 38, 39, 40).

The results of these studies in a variety of experimental systems demonstrate that the rat LH subunit genes are differentially stimulated by the two signaling pathways activated by the GnRH receptor. The relative concentrations of molecules contributing to these pathways are unknown but could vary with GnRH pulses. Even a single GnRH pulse, for example, induces internal Ca⁺⁺ oscillations in gonadotropes, suggesting complicated dynamics involving multiple cellular compartments (41). The GnRH receptor can also couple to multiple G proteins, enabling preferential associations under different GnRH concentrations and regimens to occur (23, 42). Differential signaling pathways may also be activated by the same receptor, as both the - and ß-subunits of an individual G protein can affect second messenger pathways (43, 44, 45). These results suggest a mechanism by which separate genes can be preferentially modulated by a single ligand in a physiologically relevant manner.

	MATERIALS AND METHODS

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Transcription Run-Off Assays
Dispersed pituitary cells from male CD-1 rats (200–250 g, Charles River Laboratories, Wilmington, MA) were treated for 30 min with 10^-8 M GnRH, the PKC activator PMA (10^-7 M), the L-type Ca⁺⁺ channel agonist Bay K8644 (5 x 10^-7 M) (Calbiochem, San Diego, CA), or the L-type Ca⁺⁺ channel antagonist nimodipine (10^-7 M) (46, 47). Nimodipine was added 15 min before GnRH treatment. Transcription rates of the endogenous and LHß genes were analyzed in isolated nuclei incubated with [³²P]uridine triphosphate as previously described (47, 48). Values are expressed in parts per million and are the mean ± SEM for three or four independent samples per group. Statistical significance was assessed using multiple comparisons among group means by Tukey’s wholly significant difference procedure.

Vector Preparation
The rat promoter from -411 to +77 bp relative to the transcriptional start site (see footnote 1) was generated from genomic DNA via PCR using primers specific to the rat sequence and conserved regions of the human and mouse -subunit genes (10, 11, 49). DNA was sequenced by the Sanger method (50) and subcloned into a luciferase reporter vector. For the rat LHß gene, two constructs were used. The homologous promoter construct, containing -617 to +41 bp relative to the transcriptional start site, was fused to the luciferase reporter and used in RC4B cells. A construct containing the GnRH-responsive region (-617 to -245 bp) of the rat LHß promoter fused to the tk minimal promoter and cloned into the luciferase reporter vector was used in T3 cells. The LHß gene region from -245 to -100 bp was unresponsive to GnRH in RC4B or T3 cells (data not shown), and the tk promoter was unaffected by any treatment used.

Cell Cultures and Transfections
RC4B cells express PRL and the gonadotropins, have functional GnRH receptors, and can express both the and LHß genes (51). RC4B (8 x 10⁶ cells) were incubated with 80 µg of the LHß promoter construct in a total volume of 0.8 ml Dulbecco’s PBS, transfected by electroporation at 320 mV and 960 µFarads (Bio-Rad, Richmond, CA), and divided into eight 60-mm wells. T3 cells are a clonal gonadotropin line that expresses the -subunit but not LHß or FSHß. These cells contain GnRH receptors, and the response to GnRH has been well characterized (20, 21, 22, 23, 24, 25). T3 cells were grown in DMEM with 2 mM L-glutamine, 10% FBS, 100 U/ml penicillin, and 100 µg/ml streptomycin. Cells (1 x 10⁶/60-mm well) were plated 36–48 h before CaPO₄ transfection with 5 µg of the or LHß reporter per well. Cells were transfected for 16 h, washed, and treated. For all studies, 10^-7 M GnRH or 10^-7 M of the des-gly agonist (GnRHa), 2 mM EGTA, 5 x 10^-7 M PMA, and/or 10^-7 M nimodipine were applied for 6 h, with nimodipine added 15 min before GnRH. In some experiments 50 µM PD098059 (Calbiochem, San Diego, CA), a specific MEK inhibitor, was applied 30 min before GnRH (52). Inhibition of MEK activity by PD098059 was verified in parallel studies by measuring MAPK phosphorylation with an antibody specific to the tyr-phosphorylated form (New England BioLabs, Beverly, MA). After treatments, cells were washed, collected in 250 µl lysis buffer (Promega, Madison WI), vortexed, spun for 1 min, and assayed in a Turner 20-e luminometer (Turner Designs, Mountain View, CA). Cell lysates were also used to determine protein concentrations using the colorimetric Bio-Rad protein assay system. Results are expressed as ALUs per 100 µg protein. All data were normalized and compared with untreated controls equal to 1.0. Data represent the averages of three to eight separate experiments and were analyzed using Student’s t test comparing treatment groups to respective controls.

Transgenic Mice
Mice expressing a -2.0 kb to +41 bp LHß promoter-luciferase reporter transgene were previously described (15). These animals express LHß promoter activity specifically in the pituitary, and this activity is regulated in vivo by gonadectomy, steroids, and a GnRH antagonist. Pituitaries from transgenic female mice over 5 weeks old were removed and treated as previously described (15, 48). Cells were then treated with 10^-7 M GnRH, or GnRH in addition to 10^-7 M nimodipine, or 50 µM PD098059. Nimodipine and PD were given 30 min before 4-h stimulation by GnRH. Pituitaries were processed and luciferase activity was assayed as described (15). Statistical significance was assessed using multiple comparisons by Tukey’s significant difference procedure.

	ACKNOWLEDGMENTS

 
We thank Drs. Nancy Cooke and Jean Rica of the University of Pennsylvania Transgenic Mouse Core Facility, who performed DNA injections to establish founder mouse lines. We also thank Drs. Derek Schreihofer, Suzanne Moenter, and Martin Straume for helpful discussions and careful reading of the manuscript.

	FOOTNOTES

 
Address requests for reprints to: Margaret A. Shupnik, Box 578 Health Science Center, University of Virginia, Charlottesville, Virginia 22908. e-mail: mas3x@virginia.edu.

This work was supported by NIH Grants R01 HD25719 (to M.A.S.) and NRSA F32MH10152 (to P.C.F.), the Center for Cellular and Molecular Research in Reproduction (P30 HD28934), and the National Science Foundation Center for Biological Timing (DIR 890162) at the University of Virginia.

¹ Rat glycoprotein hormone -subunit sequence submitted to GenBank. Accession number AF016702.

Received for publication October 24, 1997. Revision received November 20, 1997. Accepted for publication November 24, 1997.

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