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Trans-Modulation of the Somatostatin Type 2A Receptor Trafficking by Insulin-Regulated Aminopeptidase Decreases Limbic Seizures

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Trans-Modulation of the Somatostatin Type 2A Receptor Trafficking by Insulin-Regulated Aminopeptidase Decreases Limbic Seizures. / De Bundel, Dimitri; Fafouri, Assia; Csaba, Zsolt; Loyens, Ellen; Lebon, Sophie; El Ghouzzi, Vincent; Peineau, Stéphane; Vodjdani, Guilan; Kiagiadaki, Foteini; Aourz, Najat; Coppens, Jessica; Walrave, Laura; Portelli, Jeanelle; Vanderheyden, Patrick; Chai, Siew Yeen; Thermos, Kyriaki; Bernard, Véronique; Collingridge, Graham; Auvin, Stéphane; Gressens, Pierre; Smolders, Ilse; Dournaud, Pascal.

In: Journal of Neuroscience, Vol. 35, No. 34, 26.08.2015, p. 11960-75.

Research output: Contribution to journalArticle

Harvard

De Bundel, D, Fafouri, A, Csaba, Z, Loyens, E, Lebon, S, El Ghouzzi, V, Peineau, S, Vodjdani, G, Kiagiadaki, F, Aourz, N, Coppens, J, Walrave, L, Portelli, J, Vanderheyden, P, Chai, SY, Thermos, K, Bernard, V, Collingridge, G, Auvin, S, Gressens, P, Smolders, I & Dournaud, P 2015, 'Trans-Modulation of the Somatostatin Type 2A Receptor Trafficking by Insulin-Regulated Aminopeptidase Decreases Limbic Seizures', Journal of Neuroscience, vol. 35, no. 34, pp. 11960-75. https://doi.org/10.1523/JNEUROSCI.0476-15.2015

APA

De Bundel, D., Fafouri, A., Csaba, Z., Loyens, E., Lebon, S., El Ghouzzi, V., ... Dournaud, P. (2015). Trans-Modulation of the Somatostatin Type 2A Receptor Trafficking by Insulin-Regulated Aminopeptidase Decreases Limbic Seizures. Journal of Neuroscience, 35(34), 11960-75. https://doi.org/10.1523/JNEUROSCI.0476-15.2015

Vancouver

De Bundel D, Fafouri A, Csaba Z, Loyens E, Lebon S, El Ghouzzi V et al. Trans-Modulation of the Somatostatin Type 2A Receptor Trafficking by Insulin-Regulated Aminopeptidase Decreases Limbic Seizures. Journal of Neuroscience. 2015 Aug 26;35(34):11960-75. https://doi.org/10.1523/JNEUROSCI.0476-15.2015

Author

De Bundel, Dimitri ; Fafouri, Assia ; Csaba, Zsolt ; Loyens, Ellen ; Lebon, Sophie ; El Ghouzzi, Vincent ; Peineau, Stéphane ; Vodjdani, Guilan ; Kiagiadaki, Foteini ; Aourz, Najat ; Coppens, Jessica ; Walrave, Laura ; Portelli, Jeanelle ; Vanderheyden, Patrick ; Chai, Siew Yeen ; Thermos, Kyriaki ; Bernard, Véronique ; Collingridge, Graham ; Auvin, Stéphane ; Gressens, Pierre ; Smolders, Ilse ; Dournaud, Pascal. / Trans-Modulation of the Somatostatin Type 2A Receptor Trafficking by Insulin-Regulated Aminopeptidase Decreases Limbic Seizures. In: Journal of Neuroscience. 2015 ; Vol. 35, No. 34. pp. 11960-75.

Bibtex Download

@article{5587f7fdbf2342c8857ac27dc7cd7e2f,
title = "Trans-Modulation of the Somatostatin Type 2A Receptor Trafficking by Insulin-Regulated Aminopeptidase Decreases Limbic Seizures",
abstract = "UNLABELLED: Within the hippocampus, the major somatostatin (SRIF) receptor subtype, the sst2A receptor, is localized at postsynaptic sites of the principal neurons where it modulates neuronal activity. Following agonist exposure, this receptor rapidly internalizes and recycles slowly through the trans-Golgi network. In epilepsy, a high and chronic release of somatostatin occurs, which provokes, in both rat and human tissue, a decrease in the density of this inhibitory receptor at the cell surface. The insulin-regulated aminopeptidase (IRAP) is involved in vesicular trafficking and shares common regional distribution with the sst2A receptor. In addition, IRAP ligands display anticonvulsive properties. We therefore sought to assess by in vitro and in vivo experiments in hippocampal rat tissue whether IRAP ligands could regulate the trafficking of the sst2A receptor and, consequently, modulate limbic seizures. Using pharmacological and cell biological approaches, we demonstrate that IRAP ligands accelerate the recycling of the sst2A receptor that has internalized in neurons in vitro or in vivo. Most importantly, because IRAP ligands increase the density of this inhibitory receptor at the plasma membrane, they also potentiate the neuropeptide SRIF inhibitory effects on seizure activity. Our results further demonstrate that IRAP is a therapeutic target for the treatment of limbic seizures and possibly for other neurological conditions in which downregulation of G-protein-coupled receptors occurs.SIGNIFICANCE STATEMENT: The somatostatin type 2A receptor (sst2A) is localized on principal hippocampal neurons and displays anticonvulsant properties. Following agonist exposure, however, this receptor rapidly internalizes and recycles slowly. The insulin-regulated aminopeptidase (IRAP) is involved in vesicular trafficking and shares common regional distribution with the sst2A receptor. We therefore assessed by in vitro and in vivo experiments whether IRAP could regulate the trafficking of this receptor. We demonstrate that IRAP ligands accelerate sst2A recycling in hippocampal neurons. Because IRAP ligands increase the density of sst2A receptors at the plasma membrane, they also potentiate the effects of this inhibitory receptor on seizure activity. Our results further demonstrate that IRAP is a therapeutic target for the treatment of limbic seizures.",
keywords = "Animals, CHO Cells, Cricetinae, Cricetulus, Cystinyl Aminopeptidase, Hippocampus, Humans, Limbic System, Male, Mice, Protein Transport, Rats, Rats, Wistar, Receptors, Somatostatin, Seizures",
author = "{De Bundel}, Dimitri and Assia Fafouri and Zsolt Csaba and Ellen Loyens and Sophie Lebon and {El Ghouzzi}, Vincent and St{\'e}phane Peineau and Guilan Vodjdani and Foteini Kiagiadaki and Najat Aourz and Jessica Coppens and Laura Walrave and Jeanelle Portelli and Patrick Vanderheyden and Chai, {Siew Yeen} and Kyriaki Thermos and V{\'e}ronique Bernard and Graham Collingridge and St{\'e}phane Auvin and Pierre Gressens and Ilse Smolders and Pascal Dournaud",
note = "Copyright {\circledC} 2015 the authors 0270-6474/15/3511961-16$15.00/0.",
year = "2015",
month = "8",
day = "26",
doi = "10.1523/JNEUROSCI.0476-15.2015",
language = "English",
volume = "35",
pages = "11960--75",
journal = "Journal of Neuroscience",
issn = "0270-6474",
number = "34",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - Trans-Modulation of the Somatostatin Type 2A Receptor Trafficking by Insulin-Regulated Aminopeptidase Decreases Limbic Seizures

AU - De Bundel, Dimitri

AU - Fafouri, Assia

AU - Csaba, Zsolt

AU - Loyens, Ellen

AU - Lebon, Sophie

AU - El Ghouzzi, Vincent

AU - Peineau, Stéphane

AU - Vodjdani, Guilan

AU - Kiagiadaki, Foteini

AU - Aourz, Najat

AU - Coppens, Jessica

AU - Walrave, Laura

AU - Portelli, Jeanelle

AU - Vanderheyden, Patrick

AU - Chai, Siew Yeen

AU - Thermos, Kyriaki

AU - Bernard, Véronique

AU - Collingridge, Graham

AU - Auvin, Stéphane

AU - Gressens, Pierre

AU - Smolders, Ilse

AU - Dournaud, Pascal

N1 - Copyright © 2015 the authors 0270-6474/15/3511961-16$15.00/0.

PY - 2015/8/26

Y1 - 2015/8/26

N2 - UNLABELLED: Within the hippocampus, the major somatostatin (SRIF) receptor subtype, the sst2A receptor, is localized at postsynaptic sites of the principal neurons where it modulates neuronal activity. Following agonist exposure, this receptor rapidly internalizes and recycles slowly through the trans-Golgi network. In epilepsy, a high and chronic release of somatostatin occurs, which provokes, in both rat and human tissue, a decrease in the density of this inhibitory receptor at the cell surface. The insulin-regulated aminopeptidase (IRAP) is involved in vesicular trafficking and shares common regional distribution with the sst2A receptor. In addition, IRAP ligands display anticonvulsive properties. We therefore sought to assess by in vitro and in vivo experiments in hippocampal rat tissue whether IRAP ligands could regulate the trafficking of the sst2A receptor and, consequently, modulate limbic seizures. Using pharmacological and cell biological approaches, we demonstrate that IRAP ligands accelerate the recycling of the sst2A receptor that has internalized in neurons in vitro or in vivo. Most importantly, because IRAP ligands increase the density of this inhibitory receptor at the plasma membrane, they also potentiate the neuropeptide SRIF inhibitory effects on seizure activity. Our results further demonstrate that IRAP is a therapeutic target for the treatment of limbic seizures and possibly for other neurological conditions in which downregulation of G-protein-coupled receptors occurs.SIGNIFICANCE STATEMENT: The somatostatin type 2A receptor (sst2A) is localized on principal hippocampal neurons and displays anticonvulsant properties. Following agonist exposure, however, this receptor rapidly internalizes and recycles slowly. The insulin-regulated aminopeptidase (IRAP) is involved in vesicular trafficking and shares common regional distribution with the sst2A receptor. We therefore assessed by in vitro and in vivo experiments whether IRAP could regulate the trafficking of this receptor. We demonstrate that IRAP ligands accelerate sst2A recycling in hippocampal neurons. Because IRAP ligands increase the density of sst2A receptors at the plasma membrane, they also potentiate the effects of this inhibitory receptor on seizure activity. Our results further demonstrate that IRAP is a therapeutic target for the treatment of limbic seizures.

AB - UNLABELLED: Within the hippocampus, the major somatostatin (SRIF) receptor subtype, the sst2A receptor, is localized at postsynaptic sites of the principal neurons where it modulates neuronal activity. Following agonist exposure, this receptor rapidly internalizes and recycles slowly through the trans-Golgi network. In epilepsy, a high and chronic release of somatostatin occurs, which provokes, in both rat and human tissue, a decrease in the density of this inhibitory receptor at the cell surface. The insulin-regulated aminopeptidase (IRAP) is involved in vesicular trafficking and shares common regional distribution with the sst2A receptor. In addition, IRAP ligands display anticonvulsive properties. We therefore sought to assess by in vitro and in vivo experiments in hippocampal rat tissue whether IRAP ligands could regulate the trafficking of the sst2A receptor and, consequently, modulate limbic seizures. Using pharmacological and cell biological approaches, we demonstrate that IRAP ligands accelerate the recycling of the sst2A receptor that has internalized in neurons in vitro or in vivo. Most importantly, because IRAP ligands increase the density of this inhibitory receptor at the plasma membrane, they also potentiate the neuropeptide SRIF inhibitory effects on seizure activity. Our results further demonstrate that IRAP is a therapeutic target for the treatment of limbic seizures and possibly for other neurological conditions in which downregulation of G-protein-coupled receptors occurs.SIGNIFICANCE STATEMENT: The somatostatin type 2A receptor (sst2A) is localized on principal hippocampal neurons and displays anticonvulsant properties. Following agonist exposure, however, this receptor rapidly internalizes and recycles slowly. The insulin-regulated aminopeptidase (IRAP) is involved in vesicular trafficking and shares common regional distribution with the sst2A receptor. We therefore assessed by in vitro and in vivo experiments whether IRAP could regulate the trafficking of this receptor. We demonstrate that IRAP ligands accelerate sst2A recycling in hippocampal neurons. Because IRAP ligands increase the density of sst2A receptors at the plasma membrane, they also potentiate the effects of this inhibitory receptor on seizure activity. Our results further demonstrate that IRAP is a therapeutic target for the treatment of limbic seizures.

KW - Animals

KW - CHO Cells

KW - Cricetinae

KW - Cricetulus

KW - Cystinyl Aminopeptidase

KW - Hippocampus

KW - Humans

KW - Limbic System

KW - Male

KW - Mice

KW - Protein Transport

KW - Rats

KW - Rats, Wistar

KW - Receptors, Somatostatin

KW - Seizures

U2 - 10.1523/JNEUROSCI.0476-15.2015

DO - 10.1523/JNEUROSCI.0476-15.2015

M3 - Article

C2 - 26311777

VL - 35

SP - 11960

EP - 11975

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 34

ER -

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