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      Dynamics of Glucocorticoid Receptor and Mineralocorticoid Receptor: Implications from Live Cell Imaging Studies

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          Abstract

          Adrenal corticosteroids (cortisol in humans/corticosterone in rodents) readily enter the brain and exert markedly diverse effects, such as the stress response of target neural cells. These effects are regulated via two receptor systems, the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR), both of which are ligand-inducible transcription factors. It is generally accepted that GR and MR predominantly reside in the cytoplasm in the absence of corticosterone (CORT), and are quickly translocated into the nucleus upon binding CORT. Then these receptors form dimers to bind hormone-responsive elements and regulate the expression of target genes. Given the different actions of MR and GR in the central nervous system, it is important to elucidate how the trafficking of these receptors between the cytoplasm and nucleus and their interaction are regulated by ligands or other molecules to exert transcriptional activity. However, the precise mechanisms of these processes are still not completely clarified. To address these issues, we have tried to observe more dynamic subcellular trafficking processes in living cells by employing a green fluorescent protein. In this review, we describe our recent studies of corticosteroid receptor dynamics in living cells focusing on three points: (1) the effects of a ligand, corticosteroid; (2) the carrier molecules involved in active nuclear transport, importins, and (3) the possibility of heterodimer formation. These studies demonstrate that GR and MR were quickly translocated from the cytoplasm to the nucleus after CORT treatment by associating with importin molecules. GR and MR differed in their response to the concentration of CORT in neural cells and non-neural cells. In the nuclear region, we detected GR-MR heterodimers, which were affected by changes in CORT concentrations in response to various hormonal milieus such as circadian rhythm and stress.

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          Most cited references 25

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          Neurocircuitry of stress: central control of the hypothalamo-pituitary-adrenocortical axis.

          Integration of the hypothalamo-pituitary-adrenal stress response occurs by way of interactions between stress-sensitive brain circuitry and neuroendocrine neurons of the hypothalamic paraventricular nucleus (PVN). Stressors involving an immediate physiologic threat ('systemic' stressors) are relayed directly to the PVN, probably via brainstem catecholaminergic projections. By contrast, stressors requiring interpretation by higher brain structures ('processive' stressors) appear to be channeled through limbic forebrain circuits. Forebrain limbic sites connect with the PVN via interactions with GABA-containing neurons in the bed nucleus of the stria terminalis, preoptic area and hypothalamus. Thus, final elaboration of processive stress responses is likely to involve modulation of PVN GABAergic tone. The functional and neuroanatomical data obtained suggest that disease processes involving inappropriate stress control involve dysfunction of processive stress pathways.
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            Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport.

            Experiments with vesicles containing N-methyl-D-aspartate (NMDA) receptor 2B (NR2B subunit) show that they are transported along microtubules by KIF17, a neuron-specific molecular motor in neuronal dendrites. Selective transport is accomplished by direct interaction of the KIF17 tail with a PDZ domain of mLin-10 (Mint1/X11), which is a constituent of a large protein complex including mLin-2 (CASK), mLin-7 (MALS/Velis), and the NR2B subunit. This interaction, specific for a neurotransmitter receptor critically important for plasticity in the postsynaptic terminal, may be a regulatory point for synaptic plasticity and neuronal morphogenesis.
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              Retinoid X receptor interacts with nuclear receptors in retinoic acid, thyroid hormone and vitamin D3 signalling.

              Cellular responsiveness to retinoic acid and its metabolites is conferred through two structurally and pharmacologically distinct families of receptors: the retinoic acid receptors (RAR) and the retinoid X receptors (RXR). Here we report that the transcriptional activity of RAR and RXR can be reciprocally modulated by direct interactions between the two proteins. RAR and RXR have a high degree of cooperativity in binding to target DNA, consistent with previous reports indicating that the binding of either RAR or RXR to their cognate response elements is enhanced by factors present in nuclear extracts. RXR also interacts directly with and enhances the binding of nuclear receptors conferring responsiveness to vitamin D3 and thyroid hormone T3; the DNA-binding activities of these receptors are also stimulated by the presence of nuclear extracts. Together these data indicate that RXR has a central role in multiple hormonal signalling pathways.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2007
                June 2007
                18 April 2007
                : 85
                : 3
                : 186-192
                Affiliations
                Department of Anatomy and Neurobiology, Kyoto Prefectural University of Medicine, Kyoto, Japan
                Article
                101917 Neuroendocrinology 2007;85:186–192
                10.1159/000101917
                17446698
                © 2007 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: 3, References: 33, Pages: 7
                Categories
                Signaling Mechanisms Underlying Neuroendocrine Function

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