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

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

doi:10.1016/0006-8993(88)91412-6

Cited by 38 publications

(18 citation statements)

References 47 publications

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“…Forskolin-induced increases in cAMP levels stimulated GnRH release from fragments of the rat median eminence (13) and from GT1 cells (9). We have shown by in situ hybridization and double immunostaining that endogenous GnRH neurons express the same three CNG channel subunits expressed in GT1 cells (14).…”

Section: Discussionmentioning

confidence: 82%

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Phosphodiesterase expression targeted to gonadotropin-releasing hormone neurons inhibits luteinizing hormone pulses in transgenic rats

Paruthiyil

Majdoubi

Conti

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Experiments in the GT1 gonadotropin-releasing hormone (GnRH) cell line have shown that the cAMP signaling pathway plays a central role in regulating the excitability of the cells. Lowering cAMP levels by expressing the constitutively active cAMP-specific phosphodiesterase PDE4D1 in GT1 cells inhibited spontaneous Ca 2؉ oscillations and intrinsic pulsatile GnRH secretion. To address the role of cAMP levels in endogenous GnRH neurons, we genetically targeted expression of PDE4D1 (P) to GnRH neurons in transgenic rats (R) by using the GnRH gene promoter͞enhancer regions (G). Three lines of transgenic rats, GPR-2, -4, and -5, were established. In situ hybridization and RT-PCR studies demonstrated that transgene expression was specifically targeted to GnRH neurons. Decreased fertility was observed in female but not in male rats from all three lines. The mean luteinizing hormone (LH) levels in ovariectomized rats were significantly reduced in the GPR-4 and -5 lines but not in the GPR-2 line. In castrated male and female GPR-4 rats, the LH pulse frequency was dramatically reduced. Six of twelve GPR-4 females studied did not ovulate and had polycystic ovaries. The remaining six females ovulated, but the magnitude of the preovulatory LH surge was inhibited by 63%. These findings support the hypothesis that cAMP signaling may play a central role in regulating excitability of GnRH neurons in vivo. The GPR-4 line of transgenic rats provides a genetic model for the understanding of the role of pulsatile gonadotropin release in follicular development.T he pulsatile release of gonadotropin-releasing hormone (GnRH) underlies reproductive function in male and female mammals. Understanding the molecular mechanisms regulating pulsatile GnRH secretion has been hampered by the low number of GnRH neurons and their scattered localization throughout the preoptic area in rodents. Further complicating the understanding of these questions is the complexity of the neural connectivity of GnRH neurons. The development of the highly differentiated GT1 GnRH neuronal cell lines (1) and the demonstration that pulsatile release was an intrinsic property of the cells provided a model to study molecular events underlying pulsatile GnRH release (2-4). However, one is always faced with the problem of translating findings from an immortalized cell line to the physiological setting. We have attempted to bridge observations made in GT1 cells regarding signaling events regulating GnRH pulsatility to the physiological setting by developing a transgenic rat model. We used an established genetic approach to alter the activity of a signaling pathway that could be used in parallel experiments in GT1 cells and transgenic rats. Transgenic rats, unlike transgenic mice, permit the reliable analysis of pulsatile luteinizing hormone (LH) release that closely mimics pulsatile GnRH release in castrated animals (5).The secretion of GnRH in GT1 neurons is stimulated by elevations in cAMP levels (6-8). The stimulation of GnRH secretion by elevated cAMP levels appears to...

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Section: Discussionmentioning

confidence: 82%

“…Elevations in cAMP levels stimulated GnRH release from rat median eminence, the region containing GnRH nerve terminals (13). We demonstrated by in situ hybridization and double immunofluorescence that endogenous GnRH neurons also contain the mRNAs and proteins for all three subunits for the cAMP-gated CNG channels (14).…”

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confidence: 87%

Phosphodiesterase expression targeted to gonadotropin-releasing hormone neurons inhibits luteinizing hormone pulses in transgenic rats

Paruthiyil

Majdoubi

Conti

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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“…Experimental groups were treated with DA (10 M), or DA plus DL-propranolol (50 M, Sigma). At the end of the incubation, media were collected and frozen until assayed for cAMP (25). Results were analyzed by using one-way ANOVA followed by the Fisher's posthoc test.…”

Section: Methodsmentioning

confidence: 99%

Oocytes are a source of catecholamines in the primate ovary: Evidence for a cell–cell regulatory loop

Mayerhofer

Smith

Danilchik

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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Catecholamines, thought to derive from the extrinsic innervation of the ovary, participate in the regulation of ovarian development and mature gonadal function. Recently, intraovarian neurons containing tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, were described in the ovary of nonhuman primates. We now show that the primate ovary expresses both the genes encoding TH and dopamine ␤-hydroxylase (DBH), the key enzymes in norepinephrine (NE) biosynthesis. Ovarian neurons were identified as a site of TH and DBH gene expression, and surprisingly, oocytes were identified as an exclusive site of DBH synthesis. Oocytes contain neither TH mRNA nor protein, indicating that they are unable to synthesize dopamine (DA). They did, however, express a DA transporter gene identical to that found in human brain. The physiological relevance of this transporter system and DBH in oocytes was indicated by the ability of isolated oocytes to metabolize exogenous DA into NE. Isolated follicles containing oocytes-but not those from which the oocytes had been removed-responded to DA with an elevation in cAMP levels; this elevation was prevented by propranolol, a ␤-adrenoreceptor antagonist. The results suggest that oocytes and somatic cells are linked by a neuroendocrine loop consisting of NE synthesized in oocytes from actively transported DA and cAMP produced by somatic follicular cells in response to NE-induced ␤-adrenoreceptor activation.All three major catecholamines used as transmitters by sympathetic neurons of the peripheral nervous system are present in the mammalian ovary (1, 2). Among them, norepinephrine (NE) is the most abundant (1, 3, 4). A variety of experimental approaches have demonstrated that NE, recognized by specific receptors of the ␤ 2 -adrenergic subtype, stimulates ovarian steroidogenesis on its own and facilitates the stimulatory effect of gonadotropins on steroid production (5-7). NE also promotes follicular development (8-10). In contrast to this body of information, very little is known about the potential contribution(s) of dopamine (DA) to ovarian physiology. In one of the few studies on the subject (11), a stimulatory effect of DA on human granulosa cell steroidogenesis was blocked by propranolol, a ␤-adrenoreceptor antagonist, indicating that the effect of the catecholamine was indirect and most likely mediated by NE.It is commonly assumed that catecholamines reach the ovary exclusively via its extrinsic sympathetic innervation (12). However, ovarian denervation reduces, but does not eliminate, the content of NE in the gland (13), implying the existence of an additional source of catecholamine synthesis. That this source may be intrinsic to the ovary has been suggested by the identification of neuronal cell bodies containing immunoreactive tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, in the ovary of nonhuman primates (14). Whether this is the only, or the more important, intragonadal source of catecholamines in the primate ...

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“…cAM P was measured as reported earlier (Ojeda et al, 1988) using a rabbit anti-3Ј,5Ј-cAM P-BSA antibody (IC N Biomedicals, Costa Mesa, CA) at a 1:200 dilution. The samples and the standards were acetylated before the assay to enhance the sensitivity of detection (Brooker et al, 1979).…”

Section: Radioimmunoassaysmentioning

confidence: 99%

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

et al. 1997

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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.

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

Cited by 38 publications

References 47 publications

Phosphodiesterase expression targeted to gonadotropin-releasing hormone neurons inhibits luteinizing hormone pulses in transgenic rats

Phosphodiesterase expression targeted to gonadotropin-releasing hormone neurons inhibits luteinizing hormone pulses in transgenic rats

Oocytes are a source of catecholamines in the primate ovary: Evidence for a cell–cell regulatory loop

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

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

Cited by 38 publications

References 47 publications

Phosphodiesterase expression targeted to gonadotropin-releasing hormone neurons inhibits luteinizing hormone pulses in transgenic rats

Phosphodiesterase expression targeted to gonadotropin-releasing hormone neurons inhibits luteinizing hormone pulses in transgenic rats

Oocytes are a source of catecholamines in the primate ovary: Evidence for a cell–cell regulatory loop

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

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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