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      Recombinant Human Growth Hormone Affects the Density and Functionality of GABA B Receptors in the Male Rat Brain

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          Abstract

          The beneficial effects of growth hormone (GH) on memory and learning have previously been confirmed in both humans and in animal models. An important role of GABA<sub>B</sub> receptors for multiple forms of learning and memory has also been reported. In this study, we examined the effect of GH on the density and functionality of the metabotropic GABA<sub>B</sub> receptors in the rat brain. Male Sprague-Dawley rats (n = 24) divided into 3 groups were injected twice daily with recombinant human GH (0.07 or 0.7 IU/kg) for 7 days. The effects of the hormone were determined by quantitative autoradiography and by GABA<sub>B</sub> stimulated [<sup>35</sup>S]-GTPγS binding using the selective GABA<sub>B</sub> receptor agonist baclofen. The results demonstrate moderate but significant alterations in both receptor density and functionality in a number of brain regions. For example, a dose-dependent upregulation of GABA<sub>B</sub> receptors was found in the cingulate cortex, primary motor cortex and caudate putamen, whereas attenuation in the receptor density was encountered in, for example, the medial geniculate nucleus. Although the GH-induced effects on the GABA<sub>B</sub> receptor in brain areas associated with cognition were fairly pronounced, they were significant and we propose that the physiological responses observed after GH administration at least partly can be mediated through a mechanism involving GABA<sub>B</sub> receptors.

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          Heterodimerization is required for the formation of a functional GABA(B) receptor.

          GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter in the mammalian central nervous system, where it exerts its effects through ionotropic (GABA(A/C)) receptors to produce fast synaptic inhibition and metabotropic (GABA(B)) receptors to produce slow, prolonged inhibitory signals. The gene encoding a GABA(B) receptor (GABA(B)R1) has been cloned; however, when expressed in mammalian cells this receptor is retained as an immature glycoprotein on intracellular membranes and exhibits low affinity for agonists compared with the endogenous receptor on brain membranes. Here we report the cloning of a complementary DNA encoding a new subtype of the GABAB receptor (GABA(B)R2), which we identified by mining expressed-sequence-tag databases. Yeast two-hybrid screening showed that this new GABA(B)R2-receptor subtype forms heterodimers with GABA(B)R1 through an interaction at their intracellular carboxy-terminal tails. Upon expression with GABA(B)R2 in HEK293T cells, GABA(B)R1 is terminally glycosylated and expressed at the cell surface. Co-expression of the two receptors produces a fully functional GABA(B) receptor at the cell surface; this receptor binds GABA with a high affinity equivalent to that of the endogenous brain receptor. These results indicate that, in vivo, functional brain GABA(B) receptors may be heterodimers composed of GABA(B)R1 and GABA(B)R2.
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            Don't worry 'B' happy!: a role for GABA(B) receptors in anxiety and depression.

            GABA, the main inhibitory neurotransmitter in the brain, regulates many physiological and psychological processes. Thus, dysfunction of the GABA system is implicated in the pathophysiology of several neuropsychiatric disorders, including anxiety and depression. However, the role of GABA(B) receptors in behavioural processes related to these disorders has not been resolved. GABA(B) receptors are G-protein-coupled receptors that function as heterodimers of GABA(B(1)) and GABA(B(2)) subunits. In addition to highly selective agonists and antagonists, novel GABA(B) receptor tools have been developed recently to further assist elucidation of the role of GABA(B) receptors in CNS function. These include mice that lack functional GABA(B) receptors, and novel positive modulators of the GABA(B) receptor. In this review, we discuss evidence that points to a role of GABA(B) receptors in anxiety and depression.
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              Aspects of Growth Hormone and Insulin-Like Growth Factor-I Related to Neuroprotection, Regeneration, and Functional Plasticity in the Adult Brain

              Apart from regulating somatic growth and metabolic processes, accumulating evidence suggests that the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis is involved in the regulation of brain growth, development, and myelination. In addition, both GH and IGF-I affect cognition and biochemistry in the adult brain. Some of the effects of GH are attributable to circulating IGF-I, while others may be due to IGF-I produced locally within the brain. Some of the shared effects in common to GH and IGF-I may also be explained by cross-talk between the GH and IGF-I transduction pathways, as indicated by recent data from other cell systems. Otherwise, it also seems that GH may act directly without involving IGF-I (either circulating or locally). Plasticity in the central nervous system (CNS) may be viewed as changes in the functional interplay between the major cell types, neurons, astrocytes, and oligodendrocytes. GH and IGF-I affect all three of these cell types in several ways. Apart from the neuroprotective effects of GH and IGF-I posited in different experimental models of CNS injury, IGF-I has been found to increase progenitor cell proliferation and new neurons, oligodendrocytes, and blood vessels in the dentate gyrus of the hippocampus. It appears that the MAPK signaling pathway is required for IGF-I—stimulated proliferation in vitro, whereas the PI3K/Akt or MAPK/Erk signaling pathway appears to mediate antiapoptotic effects. The increase of IGF-I on endothelial cell phenotype may explain the increase in cerebral arteriole density observed after GH treatment. The functional role of GH and IGF-I in the adult brain will be reviewed with reference to neurotransmitters, glucose metabolism, cerebral blood flow, gap junctional communication, dendritic arborization, exercise, enriched environment, depression, learning, memory, and aging.Briefly, these findings suggest that IGF-I functions as a putative regenerative agent in the adult CNS. Hitherto less studied regarding in these aspects, GH may have similar effects, especially as it is the main regulator of IGF-I in vivo. Some of the positive cognitive features of GH treatment are likely attributable to the mechanisms reviewed here.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2013
                April 2013
                25 August 2012
                : 97
                : 3
                : 203-211
                Affiliations
                Division of Biological Research on Drug Dependence, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
                Author notes
                *Mathias Hallberg, Department of Pharmaceutical Biosciences, Division of Biological Research on Drug Dependence, Uppsala University, PO Box 591, SE-751 24 Uppsala (Sweden), Tel. +46 18 471 4141, E-Mail Mathias.Hallberg@farmbio.uu.se
                Article
                339821 Neuroendocrinology 2013;97:203-211
                10.1159/000339821
                22710737
                457b3a05-de89-4851-9909-ef82b049483e
                © 2012 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
                : 03 December 2011
                : 27 May 2012
                Page count
                Figures: 2, Tables: 2, Pages: 9
                Categories
                Original Paper

                Endocrinology & Diabetes,Neurology,Nutrition & Dietetics,Sexual medicine,Internal medicine,Pharmacology & Pharmaceutical medicine
                GABAB receptors,Growth hormone,Baclofen,Autoradiography

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