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Rasd1, a small G protein with a big role in the hypothalamic response to neuronal activation
BACKGROUND: Rasd1 is a member of the Ras family of monomeric G proteins that was first identified as a dexamethasone inducible gene in the pituitary corticotroph cell line AtT20. Using microarrays we previously identified increased Rasd1 mRNA expression in the rat supraoptic nucleus (SON) and parave...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704412/ https://www.ncbi.nlm.nih.gov/pubmed/26739966 http://dx.doi.org/10.1186/s13041-015-0182-2 |
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author | Greenwood, Michael P. Greenwood, Mingkwan Mecawi, Andre S. Antunes-Rodrigues, José Paton, Julian F. R. Murphy, David |
author_facet | Greenwood, Michael P. Greenwood, Mingkwan Mecawi, Andre S. Antunes-Rodrigues, José Paton, Julian F. R. Murphy, David |
author_sort | Greenwood, Michael P. |
collection | PubMed |
description | BACKGROUND: Rasd1 is a member of the Ras family of monomeric G proteins that was first identified as a dexamethasone inducible gene in the pituitary corticotroph cell line AtT20. Using microarrays we previously identified increased Rasd1 mRNA expression in the rat supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus in response to increased plasma osmolality provoked by fluid deprivation and salt loading. RASD1 has been shown to inhibit adenylyl cyclase activity in vitro resulting in the inhibition of the cAMP-PKA-CREB signaling pathway. Therefore, we tested the hypothesis that RASD1 may inhibit cAMP stimulated gene expression in the brain. RESULTS: We show that Rasd1 is expressed in vasopressin neurons of the PVN and SON, within which mRNA levels are induced by hyperosmotic cues. Dexamethasone treatment of AtT20 cells decreased forskolin stimulation of c-Fos, Nr4a1 and phosphorylated CREB expression, effects that were mimicked by overexpression of Rasd1, and inhibited by knockdown of Rasd1. These effects were dependent upon isoprenylation, as both farnesyltransferase inhibitor FTI-277 and CAAX box deletion prevented Rasd1 inhibition of cAMP-induced gene expression. Injection of lentiviral vector into rat SON expressing Rasd1 diminished, whereas CAAX mutant increased, cAMP inducible genes in response to osmotic stress. CONCLUSIONS: We have identified two mechanisms of Rasd1 induction in the hypothalamus, one by elevated glucocorticoids in response to stress, and one in response to increased plasma osmolality resulting from osmotic stress. We propose that the abundance of RASD1 in vasopressin expressing neurons, based on its inhibitory actions on CREB phosphorylation, is an important mechanism for controlling the transcriptional responses to stressors in both the PVN and SON. These effects likely occur through modulation of cAMP-PKA-CREB signaling pathway in the brain. |
format | Online Article Text |
id | pubmed-4704412 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-47044122016-01-08 Rasd1, a small G protein with a big role in the hypothalamic response to neuronal activation Greenwood, Michael P. Greenwood, Mingkwan Mecawi, Andre S. Antunes-Rodrigues, José Paton, Julian F. R. Murphy, David Mol Brain Research BACKGROUND: Rasd1 is a member of the Ras family of monomeric G proteins that was first identified as a dexamethasone inducible gene in the pituitary corticotroph cell line AtT20. Using microarrays we previously identified increased Rasd1 mRNA expression in the rat supraoptic nucleus (SON) and paraventricular nucleus (PVN) of the hypothalamus in response to increased plasma osmolality provoked by fluid deprivation and salt loading. RASD1 has been shown to inhibit adenylyl cyclase activity in vitro resulting in the inhibition of the cAMP-PKA-CREB signaling pathway. Therefore, we tested the hypothesis that RASD1 may inhibit cAMP stimulated gene expression in the brain. RESULTS: We show that Rasd1 is expressed in vasopressin neurons of the PVN and SON, within which mRNA levels are induced by hyperosmotic cues. Dexamethasone treatment of AtT20 cells decreased forskolin stimulation of c-Fos, Nr4a1 and phosphorylated CREB expression, effects that were mimicked by overexpression of Rasd1, and inhibited by knockdown of Rasd1. These effects were dependent upon isoprenylation, as both farnesyltransferase inhibitor FTI-277 and CAAX box deletion prevented Rasd1 inhibition of cAMP-induced gene expression. Injection of lentiviral vector into rat SON expressing Rasd1 diminished, whereas CAAX mutant increased, cAMP inducible genes in response to osmotic stress. CONCLUSIONS: We have identified two mechanisms of Rasd1 induction in the hypothalamus, one by elevated glucocorticoids in response to stress, and one in response to increased plasma osmolality resulting from osmotic stress. We propose that the abundance of RASD1 in vasopressin expressing neurons, based on its inhibitory actions on CREB phosphorylation, is an important mechanism for controlling the transcriptional responses to stressors in both the PVN and SON. These effects likely occur through modulation of cAMP-PKA-CREB signaling pathway in the brain. BioMed Central 2016-01-07 /pmc/articles/PMC4704412/ /pubmed/26739966 http://dx.doi.org/10.1186/s13041-015-0182-2 Text en © Greenwood et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Greenwood, Michael P. Greenwood, Mingkwan Mecawi, Andre S. Antunes-Rodrigues, José Paton, Julian F. R. Murphy, David Rasd1, a small G protein with a big role in the hypothalamic response to neuronal activation |
title | Rasd1, a small G protein with a big role in the hypothalamic response to neuronal activation |
title_full | Rasd1, a small G protein with a big role in the hypothalamic response to neuronal activation |
title_fullStr | Rasd1, a small G protein with a big role in the hypothalamic response to neuronal activation |
title_full_unstemmed | Rasd1, a small G protein with a big role in the hypothalamic response to neuronal activation |
title_short | Rasd1, a small G protein with a big role in the hypothalamic response to neuronal activation |
title_sort | rasd1, a small g protein with a big role in the hypothalamic response to neuronal activation |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704412/ https://www.ncbi.nlm.nih.gov/pubmed/26739966 http://dx.doi.org/10.1186/s13041-015-0182-2 |
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