Elucidation of mechanisms of the reciprocal cross talk between gonadotropin-releasing hormone and prostaglandin receptors

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Abstract

We recently described a novel GnRH receptor signaling pathway mediated by the prostaglandins (PGs) F2α and PGI2, which acts through an autocrine/paracrine modality to limit autoregulation of the GnRH receptor and inhibit LH but not FSH release. Here we further explore the cross talk between GnRH and the PG receptors. GnRH stimulates arachidonic acid (AA) release from LβT2 gonadotrope cells via the Ca2+-independent phospholipase A2 (iPLA2) and not via the more common Ca2+-dependent cytosolic phospholipase A2α (cPLA2α). AA release was followed by a marked induction of cyclooxygenase (COX)-1 and COX-2 by GnRH via the protein kinase C/c-Src/phosphatidylinositol 3-kinase/MAPK pathway. COX-2 transcription by GnRH is mediated by the two nuclear factor-κB sites and the CCAAT/enhancer-binding protein site within its promoter. Indeed, GnRH stimulates p65/RelA phosphorylation (22-fold) in LβT2 cells and the two nuclear factor-κB sites apparently act as a composite response element. Although GnRH stimulates cAMP formation in LβT2 cells, we found no role for cAMP acting via the cAMP response element site in the COX-2 promoter.PGF 2α, PGI2,or PGE2 had no effect on GnRH-stimulated ERK, c-Jun N-terminal kinase,and p38MAPK activation or on GnRH- and high K+-stimulated intracellular Ca2+ elevation in LβT2 and gonadotropes in primary culture. Although, PGF2α, PGI2, and PGE2 reduced GnRH-stimulated cAMP formation, we could not correlate it to the inhibition of GnRH receptor expression, which is exerted only by PGF2α and PGI2. Hence, the inhibition by PGF2α and PGI2 of the autoregulation of GnRH receptor expression is most likely mediated via inhibition of GnRH-stimulated phosphoinositide turnover and not by inhibition of Ca 2+ elevation and MAPK activation. Copyright © 2010 by The Endocrine Society.

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Naidich, M., Shterntal, B., Furman, R., Pawson, A. J., Jabbour, H. N., Morgan, K., … Naor, Z. (2010). Elucidation of mechanisms of the reciprocal cross talk between gonadotropin-releasing hormone and prostaglandin receptors. Endocrinology, 151(6), 2700–2712. https://doi.org/10.1210/en.2009-1335

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