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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

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.

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