Gonadotropin Releasing Hormone Activates the Lipoxygenase Pathway in Cultured Pituitary Cells: Role in Gonadotropin Secretion and Evidence for a Novel Autocrine/Paracrine Loop

Hana Dan-Cohen, Zvi Naor, Yosef Sofer, Michal L. Schwartzman, Rama D. Natarajan, Jerry L. Nadler

Research output: Contribution to journalArticlepeer-review

Abstract

The formation and role of arachidonic acid (AA) and its metabolites during gonadotropin releasing hormone-(GnRH-) induced gonadotropin secretion were investigated in primary cultures of rat pituitary cells. Prelabeled cells ([3H]AA) responded to GnRH challenge with increased formation (about 2-fold) of the leukotrienes LTC4, LTD4, and LTE4 as well as 5-and 15-eicosatetraenoic acids (5-and 15-HETE) as identified by HPLC. Formation of leukotrienes and 15-HETE was further verified by specific radioimmunoassays. No significant increase in the formation of 12-HETE or of the cyclooxygenase products prostaglandin E (PGE) and thromboxane A2 by GnRH was noticed. Addition of physiological concentrations of LTC4 enhanced basal LH release, while subphysiological concentrations of LTC4 (10-15-10-12 M) inhibited GnRH-induced LH release by about 35% (p < 0.02). Using specific lipoxygenase inhibitors L-656, 224 and MK 886, we found inhibition of GnRH-induced LH release by about 40% at concentrations known to specifically inhibit the 5-lipoxygenase pathway. The peptidoleukotriene receptor antagonist ICI 198, 615 inhibited LTC4- and LTE4- induced LH release and surprisingly also the effect of GnRH on LH release by 40%. The data strongly suggest a role for AA and its lipoxygenase metabolites in the on/off reactions of GnRH upon LH release. The data also present a novel amplification cycle in which newly formed leukotrienes become first messengers and establish an autocrine/paracrine loop.

Original languageEnglish
Pages (from-to)5442-5448
Number of pages7
JournalBiochemistry
Volume31
Issue number24
DOIs
StatePublished - 1 Feb 1992

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