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Endocrinology Vol. 139, No. 7 3104-3111
Copyright © 1998 by The Endocrine Society

ARTICLES

Gonadotropin-Releasing Hormone Pulses Are Required to Maintain Activation of Mitogen-Activated Protein Kinase: Role in Stimulation of Gonadotrope Gene Expression1

Daniel J. Haisenleder, Michael E. Cox, Sarah J. Parsons and John C. Marshall

Division of Endocrinology, Departments of Medicine and Microbiology (M.E.C., S.J.P.), University of Virginia Health Science Center, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Dr. Daniel J. Haisenleder, Division of Endocrinology, Department of Medicine, University of Virginia Health Science Center, 5041 MR-4 Building, Charlottesville, Virginia 22908. E-mail:djh2q{at}virginia.edu

The present study examined the effect of alterations in GnRH signal pattern (pulsatile vs. continuous; pulse frequency) on mitogen-activated protein kinase (MAPK) activity and whether MAPK plays a role in regulating gonadotrope gene expression. Pituitary MAPK activity was measured by immunoblot, using a phospho-specific MAPK antibody, corrected to the amount of total MAPK per sample. In vivo studies were conducted in adult castrate testosterone-replaced male rats (to suppress endogenous GnRH). Animals received pulsatile or continuous GnRH (or BSA-saline for controls) via jugular cannulas. Initial studies revealed that pulsatile GnRH stimulated a dose-dependent rise in MAPK activity (30 ng, 2-fold increase; 100 ng, 4-fold; 300 ng, 8-fold) 4 min after the pulse. The effect of pulsatile vs. continuous GnRH was examined by administering 50-ng pulses (60-min interval) or a continuous infusion (25 ng/min) for 1, 2, 4, or 8 h. Pulsatile GnRH stimulated a 2- to 4-fold rise in MAPK activity (P < 0.05 vs. controls) that was maintained over the 8-h duration. In contrast, continuous GnRH only increased MAPK activity (2- to 3-fold; P < 0.05 vs. controls) for 2 h, with MAPK activity returning to baseline at later time points. The effect of GnRH pulse frequency on MAPK activation was determined by giving GnRH pulses (50 ng) at 30-, 60-, or 120-min intervals for 8 h. Maximal increases (3-fold vs. controls; P < 0.05) were seen after 120-min pulses, with faster (30- to 60-min interval) pulses stimulating 2-fold increases in MAPK activity (P < 0.05 vs. controls and 120-min GnRH pulse group).

The role of MAPK activation on gonadotrope ({alpha}, LHß, FSHß, and GnRH receptor) gene expression was determined in vitro. Preliminary studies demonstrated that the MAPK inhibitor, PD-098059 (50 µM), completely blocked GnRH-induced increases in MAPK activity in adult male pituitary cells. Further studies revealed that PD-098059 blocked gonadotrope messenger RNA (mRNA) responses to pulsatile GnRH (100 pg/ml, 60-min interval, 24-h duration) in a selective manner, with {alpha}, FSHß, and GnRH receptor (but not LHß) mRNA responses being suppressed. These results show that a pulsatile GnRH signal is required to maintain MAPK activation for durations of longer than 2 h, and that slower frequency pulses are more effective. Further, MAPK plays a crucial role in {alpha}, FSHß, and GnRH receptor mRNA responses to pulsatile GnRH. Thus, divergent MAPK responses to alterations in GnRH signal pattern may be one mechanism involved in differential regulation of gonadotrope gene expression.




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