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Different Signaling Pathways Control Acute Induction versus Long-Term Repression of LHß Transcription by GnRH

Departments of Reproductive Medicine (V.V.V., M.A.L., P.L.M.), Neuroscience (V.V.V., P.L.M.), and Medicine (D.D., N.J.G.W.), University of California, San Diego, La Jolla, California 92093-0674; and the Medical Research Service (N.J.G.W.), San Diego VA Healthcare System, San Diego, California 92161

Address all correspondence and requests for reprints to: Dr. Pamela L. Mellon, Reproductive Medicine, 0674, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0674. E-mail: pmellon{at}ucsd.edu.

GnRH regulates pituitary gonadotropin gene expression through GnRH receptor activation of the protein kinase C (PKC) and calcium signaling cascades. The pulsatile pattern of GnRH release is crucial for induction of LHß-subunit (LHß) gene expression; however, continuous prolonged GnRH exposure leads to repression of LHß gene transcription. Although in part, long-term repression may be due to receptor down-regulation, the molecular mechanisms of this differential regulation of LHß transcription are unknown. Using transfection into the LH-secreting immortalized mouse gonadotrope cell line (LßT4), we have demonstrated that LHß gene transcription is increased by acute activation (6 h) of GnRH receptor or PKC but not calcium influx; in contrast long-term activation (24 h) of GnRH receptor, PKC, or calcium influx each repress LHß transcription. Whereas blockade of PKC prevented the acute action of GnRH and unmasked an acute repression of LHß transcription by calcium, it did not prevent long-term repression by GnRH or calcium. Removal of calcium resulted in potentiation of acute GnRH and PKC induction of LHß gene expression but prevented long-term repression by GnRH and reduced long-term repression by either calcium or 12-O-tetradecanoyl-phorbol-13-acetate (TPA). We conclude that GnRH uses PKC for acute induction, and calcium signaling is responsible for long-term repression of LHß gene expression by GnRH. Furthermore, analysis of the responsiveness of truncated and mutated LHß promoter regions demonstrated that not only do acute induction and long-term repression use different signaling systems, but they also use different target sequences for regulating the LHß gene.

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