Cetrorelix, a Gonadotropin-Releasing Hormone Antagonist, Induces the Expression of Melatonin Receptor 1a in the Gonadotropin-Releasing Hormone Neuronal Cell Line GT1–7

Ishii, Hirotaka; Sato, Shun; Yin, Chengzhu; Sakuma, Yasuo; Kato, Masakatsu

doi:10.1159/000231993

Cited by 7 publications

(4 citation statements)

References 78 publications

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“…However, despite this physiological effect, there was surprisingly no change in pituitary Mt1 expression. This finding contrasts with the ability of cetrorelix to induce MT1 receptor expression in the GT1-7 neuronal cell line [29] and suggests that changes during normal gonadotroph development maintain inhibition of Mt1 mRNA, despite the lack of GnRH signalling.…”

Section: Discussioncontrasting

confidence: 61%

Regulation of Pituitary MT1 Melatonin Receptor Expression by Gonadotrophin-Releasing Hormone (GnRH) and Early Growth Response Factor-1 (Egr-1): In Vivo and In Vitro Studies

et al. 2014

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Melatonin receptor expression exhibits profound developmental changes through poorly understood mechanisms. In mammals, a current model suggests that pubertal reactivation of gonadotrophin-releasing hormone (GnRH) secretion down-regulates MT1 melatonin receptors in pituitary gonadotroph cells, via the induction of early growth response factor-1 (EGR-1). Here we have examined this model by testing the hypotheses that inhibition of Mt1 expression by GnRH occurs directly in gonadotroph cells, can be reversed in adulthood by blockade of GnRH receptors, and requires EGR-1. We first confirmed the endogenous expression of Mt1 mRNA in the αT3-1 gonadotroph cell line. Stimulation of these cells with a GnRH agonist resulted in a rapid increase of Egr-1 mRNA expression, which peaked after 30–60 minutes, and a more prolonged elevation of nuclear EGR-1 immunoreactivity. Moreover, the GnRH agonist significantly decreased Mt1 mRNA. We then treated adult male rats with the GnRH antagonist cetrorelix or saline. After 4 weeks of daily injections, cetrorelix significantly reduced serum LH concentration and testis weight, with histological analysis confirming absence of spermatogenesis. Despite the successful inhibition of GnRH signalling, pituitary Mt1 expression was unchanged. Next we studied the proximal region of the rat Mt1 promoter. Consistent with previous work, over-expression of the transcription factor PITX-1 increased Mt1-luciferase reporter activity; this effect was dependent on the presence of consensus PITX-1 promoter binding regions. Over-expression of EGR-1 inhibited PITX-1-stimulated activity, even following mutation of the consensus EGR-1 binding site. Finally, we studied Egr1 −/− mice and observed no difference in pituitary Mt1 expression between Egr1 −/− and wild-type litter mates. This work demonstrates that GnRH receptor activation directly down-regulates Mt1 expression in gonadotroph cells. However, pituitary Mt1 expression in adults is unaltered by blockade of GnRH signalling or absence of EGR-1. Our data therefore suggest that melatonin receptor regulation by GnRH is not reversible in adulthood and doesn't require EGR-1.

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Section: Discussioncontrasting

confidence: 61%

Regulation of Pituitary MT1 Melatonin Receptor Expression by Gonadotrophin-Releasing Hormone (GnRH) and Early Growth Response Factor-1 (Egr-1): In Vivo and In Vitro Studies

et al. 2014

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“…Data represent mean ± SEM hypothalamic magnocellular peptidergic neurons [31]. In fact, we have recently shown that ambient GnRH downregulates the expression of melatonin receptors in GT1-7 cells [32].…”

Section: Discussionmentioning

confidence: 97%

Voltage-gated Ca2+ channel mRNAs and T-type Ca2+ currents in rat gonadotropin-releasing hormone neurons

et al. 2010

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Gonadotropin-releasing hormone (GnRH) neurons play a pivotal role in the neuroendocrine regulation of reproduction. We have previously reported that rat GnRH neurons exhibit voltage-gated Ca(2+) currents. In this study, oligo-cell RT-PCR was carried out to identify subtypes of the alpha(1) subunit of voltage-gated Ca(2+) channels in adult rat GnRH neurons. GnRH neurons expressed mRNAs for all five types of voltage-gated Ca(2+) channels. For T-type Ca(2+) channels, alpha(1H) was dominantly expressed in GnRH neurons. Electrophysiological analysis in acute slice preparations revealed that GnRH neurons from adult rats exhibited T-type Ca(2+) currents with fast inactivation kinetics (~20 ms at -30 mV) and a time constant of recovery from inactivation of ~0.6 s. These results indicate that rat GnRH neurons express subtypes of the alpha(1) subunit for all five types of voltage-gated Ca(2+) channel, and that alpha(1H) was the dominant subtype in T-type Ca(2+) channels.

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“…Experimental studies [32,33] have shown that an increase in testicular androgen production occurs and peaks in the late gestational period, around E18 and continues in the first days of life [34]. Much of this testosterone is aromatized into estradiol and leads to the development of sexually dimorphic areas of the brain.…”

Section: Discussionmentioning

confidence: 99%

Neonatal Testosterone Exposure Protects Adult Male Rats from Stroke

Persky

Weston

et al. 2012

Neuroendocrinology

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Background: Men have a higher stroke incidence compared to women until advanced age. The contribution of hormones to these sex differences has been extensively debated. In experimental stroke, estradiol is neuroprotective, whereas androgens are detrimental. However, prior studies have only examined the effects of acute treatment paradigms; therefore, the timing and mechanism by which ischemic sexual dimorphism arises are unknown. Methods: The effects of exogenous neonatal androgen exposure on subsequent injury induced by middle cerebral artery occlusion in adulthood in male rats were examined. Rats were administered vehicle (oil), testosterone propionate (TP) or the non-aromatizable androgen dihydrotestosterone (DHT) for 5 days after birth. At 3 months of age, a focal stroke was induced. Results: Testosterone-treated rats (but not DHT-treated animals) had decreased infarct volumes (20 vs. 33%, p < 0.05) as well as increased estradiol levels (39.4 vs. 18.6 pg/ml, p < 0.0001) compared to oil-treated animals. TP-injected males had increased testicular aromatase (P450arom) levels (3.6 vs. 0.2 ng/ml, p < 0.0001) compared to oil-treated males. The level of X-linked inhibitor of apoptosis, the primary endogenous inhibitor of caspase-induced apoptosis, was increased in TP-treated rats compared with the oil-treated males. Conclusions: Neonatal exposure to exogenous testosterone upregulates testicular aromatase expression in male rats and leads to adult neuroprotection secondary to changes in serum estradiol levels and cell death proteins. This study suggests that early exposure to gonadal hormones can have dramatic effects on the response to adult cerebrovascular injury.

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Cetrorelix, a Gonadotropin-Releasing Hormone Antagonist, Induces the Expression of Melatonin Receptor 1a in the Gonadotropin-Releasing Hormone Neuronal Cell Line GT1–7

Cited by 7 publications

References 78 publications

Regulation of Pituitary MT1 Melatonin Receptor Expression by Gonadotrophin-Releasing Hormone (GnRH) and Early Growth Response Factor-1 (Egr-1): In Vivo and In Vitro Studies

Regulation of Pituitary MT1 Melatonin Receptor Expression by Gonadotrophin-Releasing Hormone (GnRH) and Early Growth Response Factor-1 (Egr-1): In Vivo and In Vitro Studies

Voltage-gated Ca2+ channel mRNAs and T-type Ca2+ currents in rat gonadotropin-releasing hormone neurons

Neonatal Testosterone Exposure Protects Adult Male Rats from Stroke

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