Trans-Modulation of the Somatostatin Type 2A Receptor Trafficking by Insulin-Regulated Aminopeptidase Decreases Limbic Seizures.
Identifieur interne : 002969 ( PubMed/Curation ); précédent : 002968; suivant : 002970Trans-Modulation of the Somatostatin Type 2A Receptor Trafficking by Insulin-Regulated Aminopeptidase Decreases Limbic Seizures.
Auteurs : Dimitri De Bundel [Belgique] ; Assia Fafouri [France] ; Zsolt Csaba [France] ; Ellen Loyens [Belgique] ; Sophie Lebon [France] ; Vincent El Ghouzzi [France] ; Stéphane Peineau [Royaume-Uni] ; Guilan Vodjdani [France] ; Foteini Kiagiadaki [Grèce] ; Najat Aourz [Belgique] ; Jessica Coppens [Belgique] ; Laura Walrave [Belgique] ; Jeanelle Portelli [Belgique] ; Patrick Vanderheyden [Belgique] ; Siew Yeen Chai ; Kyriaki Thermos [Grèce] ; Véronique Bernard [France] ; Graham Collingridge [Royaume-Uni] ; Stéphane Auvin [France] ; Pierre Gressens [France] ; Ilse Smolders [Belgique] ; Pascal Dournaud [France]Source :
- The Journal of neuroscience : the official journal of the Society for Neuroscience [ 1529-2401 ] ; 2015.
Descripteurs français
- KwdFr :
- Animaux, Cellules CHO, Cricetinae, Cricetulus, Crises épileptiques (), Crises épileptiques (métabolisme), Cystinyl aminopeptidase (métabolisme), Hippocampe (métabolisme), Humains, Mâle, Rat Wistar, Rats, Récepteur somatostatine (métabolisme), Souris, Système limbique (métabolisme), Transport de protéines (physiologie).
- MESH :
- métabolisme : Crises épileptiques, Cystinyl aminopeptidase, Hippocampe, Récepteur somatostatine, Système limbique.
- physiologie : Transport de protéines.
- Animaux, Cellules CHO, Cricetinae, Cricetulus, Crises épileptiques, Humains, Mâle, Rat Wistar, Rats, Souris.
English descriptors
- KwdEn :
- Animals, CHO Cells, Cricetinae, Cricetulus, Cystinyl Aminopeptidase (metabolism), Hippocampus (metabolism), Humans, Limbic System (metabolism), Male, Mice, Protein Transport (physiology), Rats, Rats, Wistar, Receptors, Somatostatin (metabolism), Seizures (metabolism), Seizures (prevention & control).
- MESH :
- chemical , metabolism : Cystinyl Aminopeptidase, Receptors, Somatostatin.
- metabolism : Hippocampus, Limbic System, Seizures.
- physiology : Protein Transport.
- prevention & control : Seizures.
- Animals, CHO Cells, Cricetinae, Cricetulus, Humans, Male, Mice, Rats, Rats, Wistar.
Abstract
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.
DOI: 10.1523/JNEUROSCI.0476-15.2015
PubMed: 26311777
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Siew Yeen Chai<affiliation><nlm:affiliation>Department of Physiology, Monash University, Victoria 3052, Australia, and.</nlm:affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation>Le document en format XML
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Brussels</wicri:regionArea></affiliation></author><author><name sortKey="Chai, Siew Yeen" sort="Chai, Siew Yeen" uniqKey="Chai S" first="Siew Yeen" last="Chai">Siew Yeen Chai</name><affiliation><nlm:affiliation>Department of Physiology, Monash University, Victoria 3052, Australia, and.</nlm:affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation></author><author><name sortKey="Thermos, Kyriaki" sort="Thermos, Kyriaki" uniqKey="Thermos K" first="Kyriaki" last="Thermos">Kyriaki Thermos</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Pharmacology, Faculty of Medicine, University of Crete, Heraklion 71003, Greece.</nlm:affiliation><country xml:lang="fr">Grèce</country><wicri:regionArea>Laboratory of Pharmacology, Faculty of Medicine, University of Crete, Heraklion 71003</wicri:regionArea></affiliation></author><author><name sortKey="Bernard, Veronique" sort="Bernard, Veronique" uniqKey="Bernard V" first="Véronique" last="Bernard">Véronique Bernard</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U952, CNRS UMR7224, Université Pierre et Marie Curie, 75005 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U952, CNRS UMR7224, Université Pierre et Marie Curie, 75005 Paris</wicri:regionArea></affiliation></author><author><name sortKey="Collingridge, Graham" sort="Collingridge, Graham" uniqKey="Collingridge G" first="Graham" last="Collingridge">Graham Collingridge</name><affiliation wicri:level="1"><nlm:affiliation>MRC Centre for Synaptic Plasticity, School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>MRC Centre for Synaptic Plasticity, School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD</wicri:regionArea></affiliation></author><author><name sortKey="Auvin, Stephane" sort="Auvin, Stephane" uniqKey="Auvin S" first="Stéphane" last="Auvin">Stéphane Auvin</name><affiliation wicri:level="1"><nlm:affiliation>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris</wicri:regionArea></affiliation></author><author><name sortKey="Gressens, Pierre" sort="Gressens, Pierre" uniqKey="Gressens P" first="Pierre" last="Gressens">Pierre Gressens</name><affiliation wicri:level="1"><nlm:affiliation>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris</wicri:regionArea></affiliation></author><author><name sortKey="Smolders, Ilse" sort="Smolders, Ilse" uniqKey="Smolders I" first="Ilse" last="Smolders">Ilse Smolders</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels</wicri:regionArea></affiliation></author><author><name sortKey="Dournaud, Pascal" sort="Dournaud, Pascal" uniqKey="Dournaud P" first="Pascal" last="Dournaud">Pascal Dournaud</name><affiliation wicri:level="1"><nlm:affiliation>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France, pascal.dournaud@inserm.fr.</nlm:affiliation><country wicri:rule="url">France</country><wicri:regionArea>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 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Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels</wicri:regionArea></affiliation></author><author><name sortKey="Fafouri, Assia" sort="Fafouri, Assia" uniqKey="Fafouri A" first="Assia" last="Fafouri">Assia Fafouri</name><affiliation wicri:level="1"><nlm:affiliation>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris</wicri:regionArea></affiliation></author><author><name sortKey="Csaba, Zsolt" sort="Csaba, Zsolt" uniqKey="Csaba Z" first="Zsolt" last="Csaba">Zsolt Csaba</name><affiliation wicri:level="1"><nlm:affiliation>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris</wicri:regionArea></affiliation></author><author><name sortKey="Loyens, Ellen" sort="Loyens, Ellen" uniqKey="Loyens E" first="Ellen" last="Loyens">Ellen Loyens</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels</wicri:regionArea></affiliation></author><author><name sortKey="Lebon, Sophie" sort="Lebon, Sophie" uniqKey="Lebon S" first="Sophie" last="Lebon">Sophie Lebon</name><affiliation wicri:level="1"><nlm:affiliation>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris</wicri:regionArea></affiliation></author><author><name sortKey="El Ghouzzi, Vincent" sort="El Ghouzzi, Vincent" uniqKey="El Ghouzzi V" first="Vincent" last="El Ghouzzi">Vincent El Ghouzzi</name><affiliation wicri:level="1"><nlm:affiliation>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris</wicri:regionArea></affiliation></author><author><name sortKey="Peineau, Stephane" sort="Peineau, Stephane" uniqKey="Peineau S" first="Stéphane" last="Peineau">Stéphane Peineau</name><affiliation wicri:level="1"><nlm:affiliation>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France, MRC Centre for Synaptic Plasticity, School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France, MRC Centre for Synaptic Plasticity, School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD</wicri:regionArea></affiliation></author><author><name sortKey="Vodjdani, Guilan" sort="Vodjdani, Guilan" uniqKey="Vodjdani G" first="Guilan" last="Vodjdani">Guilan Vodjdani</name><affiliation wicri:level="1"><nlm:affiliation>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris</wicri:regionArea></affiliation></author><author><name sortKey="Kiagiadaki, Foteini" sort="Kiagiadaki, Foteini" uniqKey="Kiagiadaki F" first="Foteini" last="Kiagiadaki">Foteini Kiagiadaki</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Pharmacology, Faculty of Medicine, University of Crete, Heraklion 71003, Greece.</nlm:affiliation><country xml:lang="fr">Grèce</country><wicri:regionArea>Laboratory of Pharmacology, Faculty of Medicine, University of Crete, Heraklion 71003</wicri:regionArea></affiliation></author><author><name sortKey="Aourz, Najat" sort="Aourz, Najat" uniqKey="Aourz N" first="Najat" last="Aourz">Najat Aourz</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels</wicri:regionArea></affiliation></author><author><name sortKey="Coppens, Jessica" sort="Coppens, Jessica" uniqKey="Coppens J" first="Jessica" last="Coppens">Jessica Coppens</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels</wicri:regionArea></affiliation></author><author><name sortKey="Walrave, Laura" sort="Walrave, Laura" uniqKey="Walrave L" first="Laura" last="Walrave">Laura Walrave</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels</wicri:regionArea></affiliation></author><author><name sortKey="Portelli, Jeanelle" sort="Portelli, Jeanelle" uniqKey="Portelli J" first="Jeanelle" last="Portelli">Jeanelle Portelli</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels</wicri:regionArea></affiliation></author><author><name sortKey="Vanderheyden, Patrick" sort="Vanderheyden, Patrick" uniqKey="Vanderheyden P" first="Patrick" last="Vanderheyden">Patrick Vanderheyden</name><affiliation wicri:level="1"><nlm:affiliation>Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel, 1090 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel, 1090 Brussels</wicri:regionArea></affiliation></author><author><name sortKey="Chai, Siew Yeen" sort="Chai, Siew Yeen" uniqKey="Chai S" first="Siew Yeen" last="Chai">Siew Yeen Chai</name><affiliation><nlm:affiliation>Department of Physiology, Monash University, Victoria 3052, Australia, and.</nlm:affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation></author><author><name sortKey="Thermos, Kyriaki" sort="Thermos, Kyriaki" uniqKey="Thermos K" first="Kyriaki" last="Thermos">Kyriaki Thermos</name><affiliation wicri:level="1"><nlm:affiliation>Laboratory of Pharmacology, Faculty of Medicine, University of Crete, Heraklion 71003, Greece.</nlm:affiliation><country xml:lang="fr">Grèce</country><wicri:regionArea>Laboratory of Pharmacology, Faculty of Medicine, University of Crete, Heraklion 71003</wicri:regionArea></affiliation></author><author><name sortKey="Bernard, Veronique" sort="Bernard, Veronique" uniqKey="Bernard V" first="Véronique" last="Bernard">Véronique Bernard</name><affiliation wicri:level="1"><nlm:affiliation>Inserm U952, CNRS UMR7224, Université Pierre et Marie Curie, 75005 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm U952, CNRS UMR7224, Université Pierre et Marie Curie, 75005 Paris</wicri:regionArea></affiliation></author><author><name sortKey="Collingridge, Graham" sort="Collingridge, Graham" uniqKey="Collingridge G" first="Graham" last="Collingridge">Graham Collingridge</name><affiliation wicri:level="1"><nlm:affiliation>MRC Centre for Synaptic Plasticity, School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>MRC Centre for Synaptic Plasticity, School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD</wicri:regionArea></affiliation></author><author><name sortKey="Auvin, Stephane" sort="Auvin, Stephane" uniqKey="Auvin S" first="Stéphane" last="Auvin">Stéphane Auvin</name><affiliation wicri:level="1"><nlm:affiliation>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris</wicri:regionArea></affiliation></author><author><name sortKey="Gressens, Pierre" sort="Gressens, Pierre" uniqKey="Gressens P" first="Pierre" last="Gressens">Pierre Gressens</name><affiliation wicri:level="1"><nlm:affiliation>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris</wicri:regionArea></affiliation></author><author><name sortKey="Smolders, Ilse" sort="Smolders, Ilse" uniqKey="Smolders I" first="Ilse" last="Smolders">Ilse Smolders</name><affiliation wicri:level="1"><nlm:affiliation>Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.</nlm:affiliation><country xml:lang="fr">Belgique</country><wicri:regionArea>Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels</wicri:regionArea></affiliation></author><author><name sortKey="Dournaud, Pascal" sort="Dournaud, Pascal" uniqKey="Dournaud P" first="Pascal" last="Dournaud">Pascal Dournaud</name><affiliation wicri:level="1"><nlm:affiliation>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France, pascal.dournaud@inserm.fr.</nlm:affiliation><country wicri:rule="url">France</country><wicri:regionArea>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France</wicri:regionArea></affiliation></author></analytic><series><title level="j">The Journal of neuroscience : the official journal of the Society for Neuroscience</title><idno type="eISSN">1529-2401</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>CHO Cells</term><term>Cricetinae</term><term>Cricetulus</term><term>Cystinyl Aminopeptidase (metabolism)</term><term>Hippocampus (metabolism)</term><term>Humans</term><term>Limbic System (metabolism)</term><term>Male</term><term>Mice</term><term>Protein Transport (physiology)</term><term>Rats</term><term>Rats, Wistar</term><term>Receptors, Somatostatin (metabolism)</term><term>Seizures (metabolism)</term><term>Seizures (prevention & control)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Cellules CHO</term><term>Cricetinae</term><term>Cricetulus</term><term>Crises épileptiques ()</term><term>Crises épileptiques (métabolisme)</term><term>Cystinyl aminopeptidase (métabolisme)</term><term>Hippocampe (métabolisme)</term><term>Humains</term><term>Mâle</term><term>Rat Wistar</term><term>Rats</term><term>Récepteur somatostatine (métabolisme)</term><term>Souris</term><term>Système limbique (métabolisme)</term><term>Transport de protéines (physiologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Cystinyl Aminopeptidase</term><term>Receptors, Somatostatin</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Hippocampus</term><term>Limbic System</term><term>Seizures</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Crises épileptiques</term><term>Cystinyl aminopeptidase</term><term>Hippocampe</term><term>Récepteur somatostatine</term><term>Système limbique</term></keywords><keywords scheme="MESH" qualifier="physiologie" xml:lang="fr"><term>Transport de protéines</term></keywords><keywords scheme="MESH" qualifier="physiology" xml:lang="en"><term>Protein Transport</term></keywords><keywords scheme="MESH" qualifier="prevention & control" xml:lang="en"><term>Seizures</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>CHO Cells</term><term>Cricetinae</term><term>Cricetulus</term><term>Humans</term><term>Male</term><term>Mice</term><term>Rats</term><term>Rats, Wistar</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Cellules CHO</term><term>Cricetinae</term><term>Cricetulus</term><term>Crises épileptiques</term><term>Humains</term><term>Mâle</term><term>Rat Wistar</term><term>Rats</term><term>Souris</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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.</div></front></TEI><pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">26311777</PMID><DateCreated><Year>2015</Year><Month>08</Month><Day>28</Day></DateCreated><DateCompleted><Year>2015</Year><Month>11</Month><Day>24</Day></DateCompleted><DateRevised><Year>2017</Year><Month>11</Month><Day>10</Day></DateRevised><Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1529-2401</ISSN><JournalIssue CitedMedium="Internet"><Volume>35</Volume><Issue>34</Issue><PubDate><Year>2015</Year><Month>Aug</Month><Day>26</Day></PubDate></JournalIssue><Title>The Journal of neuroscience : the official journal of the Society for Neuroscience</Title><ISOAbbreviation>J. Neurosci.</ISOAbbreviation></Journal><ArticleTitle>Trans-Modulation of the Somatostatin Type 2A Receptor Trafficking by Insulin-Regulated Aminopeptidase Decreases Limbic Seizures.</ArticleTitle><Pagination><MedlinePgn>11960-75</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1523/JNEUROSCI.0476-15.2015</ELocationID><Abstract><AbstractText Label="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.</AbstractText><AbstractText Label="SIGNIFICANCE STATEMENT" NlmCategory="UNASSIGNED">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.</AbstractText><CopyrightInformation>Copyright © 2015 the authors 0270-6474/15/3511961-16$15.00/0.</CopyrightInformation></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>De Bundel</LastName><ForeName>Dimitri</ForeName><Initials>D</Initials><AffiliationInfo><Affiliation>Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Fafouri</LastName><ForeName>Assia</ForeName><Initials>A</Initials><AffiliationInfo><Affiliation>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Csaba</LastName><ForeName>Zsolt</ForeName><Initials>Z</Initials><AffiliationInfo><Affiliation>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Loyens</LastName><ForeName>Ellen</ForeName><Initials>E</Initials><AffiliationInfo><Affiliation>Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lebon</LastName><ForeName>Sophie</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>El Ghouzzi</LastName><ForeName>Vincent</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Peineau</LastName><ForeName>Stéphane</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France, MRC Centre for Synaptic Plasticity, School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Vodjdani</LastName><ForeName>Guilan</ForeName><Initials>G</Initials><AffiliationInfo><Affiliation>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Kiagiadaki</LastName><ForeName>Foteini</ForeName><Initials>F</Initials><Identifier Source="ORCID">http://orcid.org/0000-0003-3769-3149</Identifier><AffiliationInfo><Affiliation>Laboratory of Pharmacology, Faculty of Medicine, University of Crete, Heraklion 71003, Greece.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Aourz</LastName><ForeName>Najat</ForeName><Initials>N</Initials><AffiliationInfo><Affiliation>Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Coppens</LastName><ForeName>Jessica</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Walrave</LastName><ForeName>Laura</ForeName><Initials>L</Initials><AffiliationInfo><Affiliation>Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Portelli</LastName><ForeName>Jeanelle</ForeName><Initials>J</Initials><AffiliationInfo><Affiliation>Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Vanderheyden</LastName><ForeName>Patrick</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel, 1090 Brussels, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Chai</LastName><ForeName>Siew Yeen</ForeName><Initials>SY</Initials><AffiliationInfo><Affiliation>Department of Physiology, Monash University, Victoria 3052, Australia, and.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Thermos</LastName><ForeName>Kyriaki</ForeName><Initials>K</Initials><AffiliationInfo><Affiliation>Laboratory of Pharmacology, Faculty of Medicine, University of Crete, Heraklion 71003, Greece.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bernard</LastName><ForeName>Véronique</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>Inserm U952, CNRS UMR7224, Université Pierre et Marie Curie, 75005 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Collingridge</LastName><ForeName>Graham</ForeName><Initials>G</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-9572-5359</Identifier><AffiliationInfo><Affiliation>MRC Centre for Synaptic Plasticity, School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Auvin</LastName><ForeName>Stéphane</ForeName><Initials>S</Initials><AffiliationInfo><Affiliation>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Gressens</LastName><ForeName>Pierre</ForeName><Initials>P</Initials><Identifier Source="ORCID">http://orcid.org/0000-0002-0909-4221</Identifier><AffiliationInfo><Affiliation>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Smolders</LastName><ForeName>Ilse</ForeName><Initials>I</Initials><AffiliationInfo><Affiliation>Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dournaud</LastName><ForeName>Pascal</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France, pascal.dournaud@inserm.fr.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>MR/K023098/1</GrantID><Agency>Medical Research Council</Agency><Country>United Kingdom</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal Article</PublicationType><PublicationType UI="D013485">Research Support, Non-U.S. Gov't</PublicationType></PublicationTypeList></Article><MedlineJournalInfo><Country>United States</Country><MedlineTA>J Neurosci</MedlineTA><NlmUniqueID>8102140</NlmUniqueID><ISSNLinking>0270-6474</ISSNLinking></MedlineJournalInfo><ChemicalList><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="D017481">Receptors, Somatostatin</NameOfSubstance></Chemical><Chemical><RegistryNumber>0</RegistryNumber><NameOfSubstance UI="C106140">somatostatin receptor sst2A</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.4.11.3</RegistryNumber><NameOfSubstance UI="D010122">Cystinyl Aminopeptidase</NameOfSubstance></Chemical><Chemical><RegistryNumber>EC 3.4.11.3</RegistryNumber><NameOfSubstance UI="C105964">leucyl-cystinyl aminopeptidase</NameOfSubstance></Chemical></ChemicalList><CitationSubset>IM</CitationSubset><MeshHeadingList><MeshHeading><DescriptorName UI="D000818" MajorTopicYN="N">Animals</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D016466" MajorTopicYN="N">CHO Cells</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D006224" MajorTopicYN="N">Cricetinae</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D003412" MajorTopicYN="N">Cricetulus</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D010122" MajorTopicYN="N">Cystinyl Aminopeptidase</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006624" MajorTopicYN="N">Hippocampus</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D006801" MajorTopicYN="N">Humans</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D008032" MajorTopicYN="N">Limbic System</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="N">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D008297" MajorTopicYN="N">Male</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D051379" MajorTopicYN="N">Mice</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D021381" MajorTopicYN="N">Protein Transport</DescriptorName><QualifierName UI="Q000502" MajorTopicYN="N">physiology</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D051381" MajorTopicYN="N">Rats</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017208" MajorTopicYN="N">Rats, Wistar</DescriptorName></MeshHeading><MeshHeading><DescriptorName UI="D017481" MajorTopicYN="N">Receptors, Somatostatin</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName></MeshHeading><MeshHeading><DescriptorName UI="D012640" MajorTopicYN="N">Seizures</DescriptorName><QualifierName UI="Q000378" MajorTopicYN="Y">metabolism</QualifierName><QualifierName UI="Q000517" MajorTopicYN="Y">prevention & control</QualifierName></MeshHeading></MeshHeadingList><KeywordList Owner="NOTNLM"><Keyword MajorTopicYN="N">GPCR</Keyword><Keyword MajorTopicYN="N">insulin-regulated aminopeptidase</Keyword><Keyword MajorTopicYN="N">limbic seizures</Keyword><Keyword MajorTopicYN="N">neuropeptide</Keyword><Keyword MajorTopicYN="N">somatostatin</Keyword><Keyword MajorTopicYN="N">traffic</Keyword></KeywordList></MedlineCitation><PubmedData><History><PubMedPubDate PubStatus="entrez"><Year>2015</Year><Month>8</Month><Day>28</Day><Hour>6</Hour><Minute>0</Minute></PubMedPubDate><PubMedPubDate 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