Prostaglandin E2 releases luteinizing hormone-releasing hormone from the female juvenile hypothalamus through a Ca2+-dependent, calmodulin-independent mechanism

Sergio R. Ojeda, Henryk F. Urbanski, Kathy H. Katz, Maria E. Costa

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    34 Scopus citations


    Prostaglandin E2 (PGE2) has been implicated as a mediator of norepinephrine-induced luteinizing hormone-releasing hormone (LHRH) release from the hypothalamus. The present experiments were undertaken to examine the hypothesis that mobilization of Ca2+ from intracellular stores and cyclic AMP (cAMP) formation are involved in this effect. Incubation of median eminence (ME) nerve terminals from juvenile rats in Ca2+-free Krebs-Ringer bicarbonate buffer reduced, but failed to prevent the stimulatory effect of PGE2 on LHRH release. None of 5 calmodulin antagonists or a blocker of calmodulin-dependent kinase affected the LHRH response to PGE2. In contrast, inhibition of intracellular Ca2+ mobilization with TMB-8 or dantrolene in Ca2+-free medium prevented the LHRH releasing effect of PGE2. Similarly to PGE2, the stimulatory effect of the Ca2+ ionophore A 23187 on LHRH release was not affected by inhibition of calmodulin activity. This,however, blocked the increase in PGE2 formation induced by the ionophore. PGE2 evoked a dose-related increase in cAMP accumulation in Ca2+-containing medium and this effect was inhibited both by blockers of intracellular Ca2+ mobilization and by calmodulin antagonists. Surprisingly, removal of extracellular Ca2+ increased basal cAMP levels in the incubation medium without affecting LHRH release; PGE2 induced a further increase in cAMP which was prevented by inhibition of intracellular Ca2+ translocation. Stimulation of adenylate cyclase activity with forskolin (F) resulted in similar increases in cAMP levels both in the presence and absence of extracellular Ca2+. However, F failed to evoke LHRH release in Ca2+-free medium. The results indicate that: (a) the stimulatory effect of PGE2 on LHRH release involves mobilization of intracellular Ca2+ but not the participation of calmodulin; (b) the formation of PGE2 itself is calmodulin-dependent; (c) PGE2 stimulates cAMP formation through a calmodulin-dependent mechanism that requiied translocation of intracellular (membrane?) Ca2+; (d) the cAMP system of a population nerve terminals different from that responsive to PGE2 is normally subjected to a Ca2+-dependent inhibitory control; and (e) although PGE2 is a potent stimulator of cAMP formation in the ME and edo genously produced cAMP can induce LHRH release, in the absence of extracellular Ca2+ PGE2 stimulates LHRH release in a cAMP-independent manner.

    Original languageEnglish (US)
    Pages (from-to)339-351
    Number of pages13
    JournalBrain research
    Issue number1-2
    StatePublished - Feb 16 1988


    • Cyclic adenosine monophosphate
    • Female puberty
    • Hypothalamic development
    • Hypothalamic luteinizing hormone-releasing hormone
    • Intracellular Ca
    • Prostaglandin E

    ASJC Scopus subject areas

    • Neuroscience(all)
    • Molecular Biology
    • Clinical Neurology
    • Developmental Biology


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