Estradiol Enhances Prostaglandin E₂Receptor Gene Expression in Luteinizing Hormone-Releasing Hormone (LHRH) Neurons and Facilitates the LHRH Response to PGE₂by Activating a Glia-to-Neuron Signaling Pathway

Abstract

Prostaglandin E 2 (PGE 2 ) mediates the stimulatory effect of norepinephrine (NE) on the secretion of luteinizing hormonereleasing hormone (LHRH), the neuropeptide controlling reproductive function. In rodents, this facilitatory effect requires previous exposure to estradiol, suggesting 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 investigated 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 subtype EP1-R, which is coupled to calcium mobilization. The LHRH-producing cell line GT1-1 also contains EP1-R mRNA and, to a lesser extent, the three alternatively spliced forms of EP3-R mRNA (␣, ␤, and ␥) that encode receptors linked to inhibition and stimulation of cAMP formation. Hypothalamic astrocytes treated with estradiol produced a conditioned medium that when applied to GT1-1 cells resulted in a selective upregulation of EP1-R and EP3␥-R mRNAs. The conditioned medium 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 estradiol facilitates the effect of neurotransmitters acting via PGE 2 to stimulate LHRH release is by enhancing the glial production of substances that upregulate PGE 2 receptors on LHRH neurons. The existence of such a mechanism underscores the emerging importance of glial-neuronal communication in the control of brain neurosecretory activity.

Prostaglandin E 2 release from astrocytes triggers gonadotropin-releasing hormone (GnRH) neuron firing via EP2 receptor activation

“…38 and present study) and the finding that the selective EP2 receptor agonist butaprost mimics the effect of PGE 2 suggest that the excitatory effect of PGE 2 on GnRH neuronal activity involves the activation of EP2 receptors. This inference is supported by an earlier report showing that the stimulation of GnRH-producing GT1-7 cells with butaprost results in GnRH release (20). In addition, the attenuation of the effect of PGE 2 by the bath application of PKA inhibitors or biologically inactive cAMP is consistent with earlier findings demonstrating the coupling of the EP2 receptor to the cAMP/PKA pathway (29) and the involvement of cAMP in the intracellular mechanism underlying the stimulatory effect of PGE 2 on GnRH secretion (39).…”

“…To gain insight into the nature of the receptors that mediate the potent postsynaptic excitatory action of PGE 2 on GnRH neurons, we tested the effects of 17-phenyl trinor PGE 2 (17PT-PGE 2 ), sulprostone, and butaprost, which are EP1, EP1/EP3, and EP2 receptor agonists (29), respectively, on GnRH neuronal activity. The bath application of 17PT-PGE 2 or sulprostone at 10 μM, a concentration previously shown to promote GnRH release in GnRH-secreting cell lines (20), had no effect on GnRH neuronal activity ( Fig. 3 A and B).…”

“…It is now clear that the secretory activity of GnRH neurons is controlled by both neuronal and glial input (12,13,15,16). Whereas glutamate is a key neurotransmitter involved in the transsynaptic activation of GnRH neurons (17, 18), prostaglandin E 2 (PGE 2 ) mediates cell-cell communication between astrocytes and GnRH neurons (6,19,20). A functional connection between the two systems is demonstrated by the ability of glutamate to elicit PGE 2 release from astrocytes (21-23).…”

TTF-1, a Homeodomain-containing Transcription Factor, Participates in the Control of Body Fluid Homeostasis by Regulating Angiotensinogen Gene Transcription in the Rat Subfornical Organ

“…Astroglial cells were visualized with rabbit polyclonal antibodies against glial fibrillary acidic protein (GFAP) obtained from Dako (Carpinteria, CA) and used at a 1:500 dilution. The brains were fixed and sectioned as outlined above and then subjected to immunohistochemistry using a procedure described elsewhere (26,27). A modification to the method was the addition of a ribonuclease inhibitor to the immunoreactions.…”

Modulation of hypothalamic neuronal activity through a novel G-protein-coupled estrogen membrane receptor

“…This belief stems primarily from the fact that many of the rapid effects of E 2 can be induced by selective ERα or ERβ ligands, antagonized by the ER antagonist, ICI 182,780 or are lost in animals bearing mutations in ERα and/or ERβ genes [15,46,[49][50][51][52]. In ERα-deficient mice, rapid estrogen responses in certain regions of the mouse brain are lost [53], whereas the rapid action of estradiol in mouse hippocampal and arcuate neurons is not [18,54]. Thus, there remains conflicting indications of the role of ERα and/or ERβ in rapid estrogen responses.…”