Mechanism of action of gonadotropin-releasing hormone. Involvement of phospholipid turnover in luteinizing hormone release.
The action of gonadotropin-releasing hormone (GnRH) upon luteinizing hormone (LH) secretion is calcium-dependent, but is not mediated by cyclic AMP, cyclic GMP, or prostaglandins. The role of calcium-mediated phospholipid turnover in GnRH action was investigated in 2-day cultured pituitary cells, in which the production and target cell effects of arachidonic acid were analyzed in relation to GnRH-stimulated LH release. Addition of 10(-8) M GnRH, which stimulated LH release 5-fold, caused a 35% increase in the rate of [3H]arachidonic acid release from prelabeled phospholipids. The effects of GnRH on arachidonic acid and LH release, which occurred within 10 min, were calcium-dependent and were not accompanied by a change in [3H]prostaglandin formation. The phospholipase A2 inhibitors, chloroquine and quinacrine, prevented the effect of GnRH on arachidonic acid formation and LH release. Addition of exogenous arachidonic acid or phorbol myristate acetate (which increases endogenous arachidonic acid) caused a dose-related release of LH, whereas prostaglandin E2 had no effect. Although GnRH action was highly calcium-dependent, stimulation of LH release by arachidonic acid was unaltered in the absence of extracellular calcium. The effect of arachidonic acid on LH release did not depend on conversion to prostaglandins and was not additive with the action of a maximal stimulating concentration of GnRH. These results demonstrate that GnRH increases arachidonic acid formation from the phospholipids of pituitary gonadotrophs, and indicate that the fatty acid or its metabolites can initiate LH release.
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D007700:Kinetics; D007986:Luteinizing Hormone / Q000378:metabolism*; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism*; D011796:Quinacrine / Q000494:pharmacology; D051381:Rats
D001095:Arachidonic Acids; D007987:Gonadotropin-Releasing Hormone; D002738:Chloroquine; D007986:Luteinizing Hormone; D010741:Phospholipases A; D054467:Phospholipases A2; D011796:Quinacrine; D002118:Calcium; D007213:Indomethacin