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      Internalization of Sex Hormone-Binding Globulin into Neurons and Brain Cells in vitro and in vivo

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          Abstract

          Background: Sex hormone-binding globulin (SHBG) is a 94-kDa homodimer that binds steroids and is made in the hypothalamus. We have demonstrated that infusions of SHBG into the hypothalami of rats increase their female sexual receptivity except when SHBG is coupled to dihydrotestosterone (DHT) suggesting that SHBG has an active function in behavioral neuroendocrinology. Methods: This study examines the possibility that SHBG is internalized by neuronal and/or non-neuronal brain cells as one possible mode of action using in vitro and in vivo techniques. Results: First, analysis of the uptake of radiolabeled SHBG (<sup>125</sup>I-SHBG) found <sup>125</sup>I-SHBG uptake in HT22 hippocampal cells stably transfected with cDNA for ERβ (HT22-ERβ). The addition of DHT to <sup>125</sup>I-SHBG significantly inhibited <sup>125</sup>I-SHBG uptake in HT22-ERβ cells but not in HT22-ERα or HT22 wild-type cells. SHBG internalization was specific as it did not occur in either the human neuroblastoma cell line SK-N-SH or the glioma cell line C6. Second, SHBG was labeled with a fluor (Alexa-555<sup>TM</sup>), and infused into the lateral cerebroventricles of ovariectomized rats. Optimal SHBG uptake was seen 10 min after these infusions. SHBG uptake was seen in specific parts of the choroid plexus and periventricular cells as well as into cells in the paraventricular nucleus, the medial forebrain bundle, and the habenula. Conclusions: These studies suggest that SHBG is internalized by brain cells, which may be affected by the presence of ERβ. The gonadal steroids have numerous effects in brain and the discovery that the steroid-binding protein SHBG is taken up into neurons and brain cells may demand a change in thinking about how steroids are delivered to brain cells to affect neurophysiology.

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          Most cited references 47

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          Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF.

          Estrogen rapidly activates the mitogen-activated protein kinases, Erk-1 and Erk-2, via an as yet unknown mechanism. Here, evidence is provided that estrogen-induced Erk-1/-2 activation occurs independently of known estrogen receptors, but requires the expression of the G protein-coupled receptor homolog, GPR30. We show that 17beta-estradiol activates Erk-1/-2 not only in MCF-7 cells, which express both estrogen receptor alpha (ER alpha) and ER beta, but also in SKBR3 breast cancer cells, which fail to express either receptor. Immunoblot analysis using GPR30 peptide antibodies showed that this estrogen response was associated with the presence of GPR30 protein in these cells. MDA-MB-231 breast cancer cells (ER alpha-, ER beta+) are GPR30 deficient and insensitive to Erk-1/-2 activation by 17beta-estradiol. Transfection of MDA-MB-231 cells with a GPR30 complementary DNA resulted in overexpression of GPR30 protein and conversion to an estrogen-responsive phenotype. In addition, GPR30-dependent Erk-1/-2 activation was triggered by ER antagonists, including ICI 182,780, yet not by 17alpha-estradiol or progesterone. Consistent with acting through a G protein-coupled receptor, estradiol signaling to Erk-1/-2 occurred via a Gbetagamma-dependent, pertussis toxin-sensitive pathway that required Src-related tyrosine kinase activity and tyrosine phosphorylation of tyrosine 317 of the Shc adapter protein. Reinforcing this idea, estradiol signaling to Erk-1/-2 was dependent upon trans-activation of the epidermal growth factor (EGF) receptor via release of heparan-bound EGF (HB-EGF). Estradiol signaling to Erk-1/-2 could be blocked by: 1) inhibiting EGF-receptor tyrosine kinase activity, 2) neutralizing HB-EGF with antibodies, or 3) down-modulating HB-EGF from the cell surface with the diphtheria toxin mutant, CRM-197. Our data imply that ER-negative breast tumors that continue to express GPR30 may use estrogen to drive growth factor-dependent cellular responses.
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            An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D3.

            Steroid hormones may enter cells by diffusion through the plasma membrane. However, we demonstrate here that some steroid hormones are taken up by receptor-mediated endocytosis of steroid-carrier complexes. We show that 25-(OH) vitamin D3 in complex with its plasma carrier, the vitamin D-binding protein, is filtered through the glomerulus and reabsorbed in the proximal tubules by the endocytic receptor megalin. Endocytosis is required to preserve 25-(OH) vitamin D3 and to deliver to the cells the precursor for generation of 1,25-(OH)2 vitamin D3, a regulator of the calcium metabolism. Megalin-/- mice are unable to retrieve the steroid from the glomerular filtrate and develop vitamin D deficiency and bone disease.
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              A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A.

               Hui Sun,  J. Yu,  Jane Hu (2007)
              Vitamin A has diverse biological functions. It is transported in the blood as a complex with retinol binding protein (RBP), but the molecular mechanism by which vitamin A is absorbed by cells from the vitamin A-RBP complex is not clearly understood. We identified in bovine retinal pigment epithelium cells STRA6, a multitransmembrane domain protein, as a specific membrane receptor for RBP. STRA6 binds to RBP with high affinity and has robust vitamin A uptake activity from the vitamin A-RBP complex. It is widely expressed in embryonic development and in adult organ systems. The RBP receptor represents a major physiological mediator of cellular vitamin A uptake.
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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
                September 2007
                06 August 2007
                : 86
                : 2
                : 84-93
                Affiliations
                aDepartment of Biomedical Sciences, University of Illinois College of Medicine, Rockford, Ill., bOregon Health Sciences Center, Portland, Oreg., USA; cDepartment of Anatomy, University of Jena, Jena, Germany
                Article
                107072 Neuroendocrinology 2007;86:84–93
                10.1159/000107072
                17684316
                © 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: 4, Tables: 1, References: 54, Pages: 10
                Categories
                Hormone Actions in the Brain

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