ESTRADIOL ENHANCES PROSTAGLANDIN E-2 RECEPTOR GENE-EXPRESSION IN LUTEINIZING-HORMONE-RELEASING HORMONE (LHRH) NEURONS AND FACILITATES THE LHRH RESPONSE TO PGE(2) BY ACTIVATING A GLIA-TO-NEURON SIGNALING PATHWAY

Prostaglandin E-2 (PGE(2)) mediates the stimulatory effect of norepine phrine (NE) on the secretion of luteinizing hormone-releasing hormone (LHRH), the neuropeptide controlling reproductive function. In rodents , this facilitatory effect requires previous exposure to estradiol, su ggesting that the steroid affects downstream components in the cascade that leads to PGE(2)-induced LHRH release. Because astroglia are the predominant cell type contacting LHRH-secreting nerve terminals, we in vestigated the involvement of hypothalamic astrocytes in the estradiol facilitation of PGE(2)-induced LHRH release, A subpopulation of LHRH neurons was found to express the mRNA encoding the PGE(2) receptor sub type EP1-R, which is coupled to calcium mobilization. The LHRH-produci ng cell line GT1-1 also contains EP1-R mRNA and, to a lesser extent, t he three alternatively spliced forms of EP3-R mRNA (alpha, beta, and g amma) that encode receptors linked to inhibition and stimulation of cA MP formation. Hypothalamic astrocytes treated with estradiol produced a conditioned medium that when applied to GT1-1 cells resulted in a se lective upregulation of EP1-R and EP3 gamma-R mRNAs, The conditioned m edium also enhanced the LHRH response to EP1-R and EP3-R agonists and the cAMP response to EP3-R activation. Thus, one mechanism by which es tradiol facilitates the effect of neurotransmitters acting via PGE(2) to stimulate LHRH release is by enhancing the glial production of subs tances that upregulate PGE(2) receptors on LHRH neurons, The existence of such a mechanism underscores the emerging importance of glial-neur onal communication in the control of brain neurosecretory activity.