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      Agonist-Specific Coupling of Growth Hormone Secretagogue Receptor Type 1a to Different Intracellular Signaling Systems

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          Abstract

          The growth hormone secretagogue receptor subtype 1a (GHSR-1a) is involved in biological actions of ghrelin by triggering intracellular second messengers coupled to heterotrimeric G-protein complex involving Gα<sub>q/11</sub>. Adenosine is a partial agonist of the GHSR-1a, binding to a binding pocket distinct from the one described for ghrelin. This suggests a variety of functions for the poorly understood GHSR1a receptor. In this work, a sequential analysis of the pathways involved in the regulation of GHSR-1a signaling was undertaken to characterize the intracellular calcium mobilization that is observed following adenosine binding. The results showed that adenosine induced, in a dose-dependent manner, a calcium mobilization from IP<sub>3</sub>-sensitive intracellular stores since the IP<sub>3</sub> receptor blocker 2-APB was able to suppress the calcium response. However, adenosine did not show any effect in the formation of inositol phosphates. The calcium-mobilizing activity was blocked after preincubation of cells with CTX, the inhibitor of adenylate cyclase MDL-12,330A and the protein kinase A blocker H-89. Furthermore, the administration of adenosine stimulated cAMP production. Based on the experimental data, a signaling pathway is proposed involving adenylate cyclase and protein kinase A, which causes phosphorylation of the IP<sub>3</sub> receptor, with a cross-talk between the signaling pathways activated by ghrelin and adenosine. The data described in this report suggest that GHSR-1a is able to activate different intracellular second-messenger systems depending on the agonist that activates it. The regulation of the ghrelin-activated earliest signaling pathways by adenosine may have unexpected implications in the GHSR-1a actions.

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          Most cited references17

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          Specificity and mechanism of action of some commonly used protein kinase inhibitors.

          The specificities of 28 commercially available compounds reported to be relatively selective inhibitors of particular serine/threonine-specific protein kinases have been examined against a large panel of protein kinases. The compounds KT 5720, Rottlerin and quercetin were found to inhibit many protein kinases, sometimes much more potently than their presumed targets, and conclusions drawn from their use in cell-based experiments are likely to be erroneous. Ro 318220 and related bisindoylmaleimides, as well as H89, HA1077 and Y 27632, were more selective inhibitors, but still inhibited two or more protein kinases with similar potency. LY 294002 was found to inhibit casein kinase-2 with similar potency to phosphoinositide (phosphatidylinositol) 3-kinase. The compounds with the most impressive selectivity profiles were KN62, PD 98059, U0126, PD 184352, rapamycin, wortmannin, SB 203580 and SB 202190. U0126 and PD 184352, like PD 98059, were found to block the mitogen-activated protein kinase (MAPK) cascade in cell-based assays by preventing the activation of MAPK kinase (MKK1), and not by inhibiting MKK1 activity directly. Apart from rapamycin and PD 184352, even the most selective inhibitors affected at least one additional protein kinase. Our results demonstrate that the specificities of protein kinase inhibitors cannot be assessed simply by studying their effect on kinases that are closely related in primary structure. We propose guidelines for the use of protein kinase inhibitors in cell-based assays.
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            PKA Phosphorylation Dissociates FKBP12.6 from the Calcium Release Channel (Ryanodine Receptor)

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              Immunolocalization of ghrelin and its functional receptor, the type 1a growth hormone secretagogue receptor, in the cyclic human ovary.

              Ghrelin is a novel 28-amino acid peptide identified as the endogenous ligand for the GH secretagogue receptor (GHS-R). Besides its hallmark central neuroendocrine effects in the control of GH secretion and food intake, an unexpected reproductive facet of ghrelin has recently emerged because expression of this molecule and its cognate receptor has been demonstrated in rat testis. However, whether this signaling system is present in human gonads remains to be evaluated. In this study, we have assessed the presence and cellular location of ghrelin and its functional receptor, namely the type 1a GHS-R, in the cyclic human ovary by means of immunohistochemistry using specific polyclonal antibodies. Strong ghrelin immunostaining was demonstrated in ovarian hilus interstitial cells. In contrast, ghrelin signal was not detected in ovarian follicles at any developmental stage, nor was it present in newly formed corpora lutea (CL) at very early development. However, specific ghrelin immunoreactivity was clearly observed in young and mature CL, whereas expression of the peptide disappeared in regressing luteal tissue. Concerning the cognate receptor, ovarian expression of GHS-R1a protein showed a wider pattern of tissue distribution, with detectable specific signal in oocytes as well as somatic follicular cells; luteal cells from young, mature, old, and regressing CL; and interstitial hilus cells. Of particular note, follicular GHS-R1a peptide expression paralleled follicle development with stronger immunostaining in granulosa and theca layers of healthy antral follicles. In conclusion, our results are the first to demonstrate that ghrelin and its functional type 1a receptor are expressed in the cyclic human ovary with distinct patterns of cellular location. The presence of both components (ligand and receptor) of the ghrelin signaling system within the human ovary opens up the possibility of a potential regulatory role of this novel molecule in ovarian function under physiological and pathophysiological conditions.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2004
                January 2004
                02 February 2004
                : 79
                : 1
                : 13-25
                Affiliations
                aDepartment of Medicine, Research Area, Molecular Endocrinology Laboratory, Complejo Hospitalario Universitario de Santiago (CHUS) and University of Santiago de Compostela, Santiago de Compostela, Spain; bHuffington Center on Aging and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Tex., USA
                Article
                76042 Neuroendocrinology 2004;79:13–25
                10.1159/000076042
                14755130
                4206d58a-6e64-4035-b14c-56e2c831dcf9
                © 2004 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.

                History
                : 24 July 2003
                : 27 November 2003
                Page count
                Figures: 10, References: 41, Pages: 13
                Categories
                Regulation of Growth Hormone

                Endocrinology & Diabetes,Neurology,Nutrition & Dietetics,Sexual medicine,Internal medicine,Pharmacology & Pharmaceutical medicine
                Inositol triphosphate,Protein kinases,Ghrelin,Growth hormone secretagogue receptors,Calcium,cAMP,Adenosine

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