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      Dual Effect of Melatonin on Gonadotropin-Releasing-Hormone-Induced Ca 2+ Signaling in Neonatal Rat Gonadotropes

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          Abstract

          In neonatal rat gonadotropes, melatonin inhibits gonadotropin-releasing-hormone (GnRH)-stimulated increase in intracellular Ca<sup>2+</sup> concentration ([Ca<sup>2+</sup>]<sub>i</sub>); in cells transfected with the Mel1a melatonin receptor, however, melatonin has been shown to potentiate agonist-stimulated [Ca<sup>2+</sup>]<sub>i</sub> increase. To elucidate this discrepancy, we investigated the effects of melatonin in neonatal gonadotropes over a wide range of melatonin concentrations. Nystatin perforated patch recording of Ca<sup>2+</sup>-dependent potassium currents was used to monitor GnRH-induced [Ca<sup>2+</sup>]<sub>i</sub> changes. In 32% of cells, increasing melatonin concentrations in the range of 1 p M to 100 n M prolonged the latency of, and inhibited GnRH (10 n M)-stimulated [Ca<sup>2+</sup>]<sub>i</sub> increases in a concentration-dependent manner. In the remaining 68% of cells, the Ca<sup>2+</sup> increase elicited by exposure to 10 n M GnRH was also inhibited by picomolar concentrations of melatonin, but at nanomolar concentrations the inhibitory effect disappeared and melatonin was only able to prolong the latency of the response. This dual effect of melatonin however was not observed in cells stimulated with lower (2 n M) GnRH concentrations; in that case, melatonin was inhibitory at all concentrations tested with an IC<sub>50</sub> of about 30 p M. In contrast, application of nanomolar concentrations of melatonin resulted in potentiation of the GnRH-induced Ca<sup>2+</sup> increase in a small population of gonadotropes which did not respond by inhibition or prolonged latency. These results indicate that in neonatal gonadotropes, melatonin has both inhibitory and potentiating effects on GnRH-stimulated [Ca<sup>2+</sup>]<sub>i</sub> increases. Ranges of concentrations needed to produce either effect suggest that two distinct G proteins may be involved, as already observed in transfected cells.

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          Most cited references 9

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          Hypothalamic melatonin receptor sites revealed by autoradiography.

          125I-Melatonin was used to localize and characterize the melatonin receptor sites in the rat hypothalamus. Autoradiography revealed that displaceable 125I-melatonin binding occurred in suprachiasmatic nuclei and median eminence only. Further studies performed on crude membrane fractions from median eminences revealed high affinity (Kd = 21 pM) melatonin binding sites (Bmax = 8.5 fmol/mg protein). The order of potency of various indole amines to inhibit 125I-melatonin binding was melatonin much greater than N-acetyl-5-hydroxytryptamine greater than 5-methoxytryptamine greater than 5-hydroxytryptamine.
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            Gonadotropin-releasing hormone receptor initiates multiple signaling pathways by exclusively coupling to G(q/11) proteins.

            The agonist-bound gonadotropin-releasing hormone (GnRH) receptor engages several distinct signaling cascades, and it has recently been proposed that coupling of a single type of receptor to multiple G proteins (G(q), G(s), and G(i)) is responsible for this behavior. GnRH-dependent signaling was studied in gonadotropic alphaT3-1 cells endogenously expressing the murine receptor and in CHO-K1 (CHO#3) and COS-7 cells transfected with the human GnRH receptor cDNA. In all cell systems studied, GnRH-induced phospholipase C activation and Ca(2+) mobilization was pertussis toxin-insensitive, as was GnRH-mediated extracellular signal-regulated kinase activation. Whereas the G(i)-coupled m2 muscarinic receptor interacted with a chimeric G(s) protein (G(s)i5) containing the C-terminal five amino acids of Galpha(i2), the human GnRH receptor was unable to activate the G protein chimera. GnRH challenge of alphaT3-1, CHO#3 and of GnRH receptor-expressing COS-7 cells did not result in agonist-dependent cAMP formation. GnRH challenge of CHO#3 cells expressing a cAMP-responsive element-driven firefly luciferase did not result in increased reporter gene expression. However, coexpression of the human GnRH receptor and adenylyl cyclase I in COS-7 cells led to clearly discernible GnRH-dependent cAMP formation subsequent to GnRH-elicited rises in [Ca(2+)](i). In alphaT3-1 and CHO#3 cell membranes, addition of [alpha-(32)P]GTP azidoanilide resulted in GnRH receptor-dependent labeling of Galpha(q/11) but not of Galpha(i), Galpha(s) or Galpha(12/13) proteins. Thus, the murine and human GnRH receptors exclusively couple to G proteins of the G(q/11) family. Multiple GnRH-dependent signaling pathways are therefore initiated downstream of the receptor/G protein interface and are not indicative of a multiple G protein coupling potential of the GnRH receptor.
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              Melatonin inhibits cyclic AMP and cyclic GMP accumulation in the rat pituitary.

              Subnanomolar concentrations of melatonin inhibit cyclic AMP and cyclic GMP accumulation in neonatal rat anterior pituitary stimulated in vitro with luteinizing-hormone releasing-hormone. Melatonin also inhibited forskolin-stimulated cyclic AMP accumulation in pars tuberalis. Inhibition of cyclic AMP accumulation is specific for melatonin, since its analogs N-acetylserotonin and 5-methoxytryptamine are 1000 times less potent. Cyclic nucleotides may thus serve as second messengers transducing the effect of melatonin on cellular level.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2001
                October 2001
                05 October 2001
                : 74
                : 4
                : 262-269
                Affiliations
                Institute of Physiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic
                Article
                54693 Neuroendocrinology 2001;74:262–269
                10.1159/000054693
                11598382
                © 2001 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 4, References: 52, Pages: 8
                Categories
                Signaling Mechanisms

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