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      Role of Phosphodiesterases in the Regulation of Gonadotropin- Releasing Hormone Secretion in GT1 Cells

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          Increases in the level of cAMP stimulate the secretion of GnRH from GT1 GnRH neuronal cells. We hypothesized that cyclic nucleotide phosphodiesterases (PDEs), the enzymes that hydrolyze cAMP, may constitute a negative feedback signaling mechanism for GnRH regulation by decreasing the level of cAMP. GT1 cells were shown to express three PDEs by RT-PCR analysis: the cAMP-specific PDE4B and PDE4D and the calmodulin-dependent PDE1B. A splice variant of PDE4D, PDE4D3, which is activated when phosphorylated by cAMP-dependent protein kinase (PKA), was identified in GT1 cells by Western analysis. Consistent with PDEs negatively regulating GnRH secretion, treatment with the nonselective PDE inhibitor, IBMX, stimulated GnRH secretion 137% in 30-min static cultures. Furthermore, treatment with the PDE4-specific inhibitors Rolipram and RS-25344 increased GnRH secretion 48 and 125%, while treatment with the PDE1-specific inhibitor 8-MeoM-IBMX only caused a modest increase of 28%. In perifusion studies a rapid multi-fold stimulation of GnRH secretion was observed following treatment with IBMX, Rolipram or RS-25344. In conclusion, the level of PDE activity appears to be an important negative feedback signal for GnRH secretion. We hypothesize that activation of PDE4D3 by PKA may constitute a negative feedback signaling pathway which participates in the regulation of cAMP levels.

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          Origin of luteinizing hormone-releasing hormone neurons.

          Neurons expressing luteinizing hormone-releasing hormone (LHRH), found in the septal-preoptic nuclei and hypothalamus, control the release of gonadotropic hormones from the anterior pituitary gland and facilitate reproductive behaviour. LHRH-expressing neurons are also found in the nervus terminalis, a cranial nerve that is a part of the accessory olfactory system and which projects directly from the nose to the septal-preoptic nuclei in the brain. During development, LHRH-immunoreactivity is detected in the peripheral parts of the nervus terminalis before it is found in the brain. Using a combination of LHRH immunocytochemistry and tritiated thymidine autoradiography in fetal mice, we show that LHRH neurons originate in the medial olfactory placode of the developing nose, migrate across the nasal septum and enter the forebrain with the nervus terminalis, arching into the septal-preoptic area and hypothalamus. Clinically, this migratory route for LHRH-expressing neurons could explain the deficiency of gonadotropins seen in 'Kallmann's syndrome' (hypogonadotropic hypogonadism with anosmia).
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            Segmentation and the origin of regional diversity in the vertebrate central nervous system

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              Phosphorylation and Activation of a cAMP-specific Phosphodiesterase by the cAMP-dependent Protein Kinase


                Author and article information

                S. Karger AG
                December 1998
                18 December 1998
                : 68
                : 6
                : 365-373
                a Department of Obstetrics, Gynecology and Reproductive Sciences, University of California School of Medicine, San Francisco, Calif. and b Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University Medical Center, Stanford, Calif., USA
                54386 Neuroendocrinology 1998;68:365–373
                © 1998 S. Karger AG, Basel

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                Page count
                Figures: 5, References: 37, Pages: 9
                Gonadotropin-Releasing Hormone and Regulation of the Gonadal Axis


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