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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 (
, 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 , 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 , 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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