Differential gonadotropin-releasing hormone stimulation of rat luteinizing hormone subunit gene transcription by calcium influx and mitogen-activated protein kinase-signaling pathways

被引:102
作者
Weck, J
Fallest, PC
Pitt, LK
Shupnik, MA [1 ]
机构
[1] Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA
[2] Univ Virginia, Dept Med, Div Endocrinol, Charlottesville, VA 22908 USA
[3] Univ Virginia, Natl Sci Fdn, Ctr Biol Timing, Charlottesville, VA 22908 USA
关键词
D O I
10.1210/me.12.3.451
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 alpha- and LH beta-subunits in rat pituitary cells was stimulated by GnRH. Independent PKC activation by phorbol myristate acid stimulated only the alpha-subunit gene. In contrast, an L-channel antagonist (nimodipine) inhibited only LH beta stimulation by GnRH, and an L-channel agonist (BayK 8644) stimulated only basal LH beta transcription. GnRH induction of a rat alpha-subunit promoter construct in alpha T3 cells was unaffected by nimodipine or elimination of external calcium, while both treatments eliminated the LH beta response. Application of a mitogen-activated kinase kinase (MEK) inhibitor (PD098059) decreased basal and GnRH-stimulated alpha-subunit promoter activity and had no effect on LH beta promoter activity. In pituitary cells from mice bearing an LH beta promoter-luciferase reporter transgene, GnRH stimulation was inhibited by nimodipine but not by PD098059. Thus, GnRH induction and basal control of the alpha-subunit gene seem to occur through the PKC/mitogen-activated protein kinase pathway, while induction of the LH beta 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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页码:451 / 457
页数:7
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