title: Trans-Modulation of the Somatostatin Type 2A Receptor Trafficking by Insulin-Regulated Aminopeptidase Decreases Limbic Seizures.
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.
  
  
  CONCLUSIONS
  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.
authors: Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.
authors: Dimitri
authors: D
authors: De Bundel
authors: Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.
authors: Assia
authors: A
authors: Fafouri
authors: Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.
authors: Zsolt
authors: Z
authors: Csaba
authors: Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.
authors: Ellen
authors: E
authors: Loyens
authors: Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.
authors: Sophie
authors: S
authors: Lebon
authors: Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.
authors: Vincent
authors: V
authors: El Ghouzzi
authors: 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.
authors: Stéphane
authors: S
authors: Peineau
authors: Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.
authors: Guilan
authors: G
authors: Vodjdani
authors: Laboratory of Pharmacology, Faculty of Medicine, University of Crete, Heraklion 71003, Greece.
authors: Foteini
authors: http://orcid.org/0000-0003-3769-3149
authors: F
authors: Kiagiadaki
authors: Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.
authors: Najat
authors: N
authors: Aourz
authors: Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.
authors: Jessica
authors: J
authors: Coppens
authors: Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.
authors: Laura
authors: L
authors: Walrave
authors: Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.
authors: Jeanelle
authors: J
authors: Portelli
authors: Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel, 1090 Brussels, Belgium.
authors: Patrick
authors: P
authors: Vanderheyden
authors: Department of Physiology, Monash University, Victoria 3052, Australia, and.
authors: Siew Yeen
authors: SY
authors: Chai
authors: Laboratory of Pharmacology, Faculty of Medicine, University of Crete, Heraklion 71003, Greece.
authors: Kyriaki
authors: K
authors: Thermos
authors: Inserm U952, CNRS UMR7224, Université Pierre et Marie Curie, 75005 Paris, France.
authors: Véronique
authors: V
authors: Bernard
authors: MRC Centre for Synaptic Plasticity, School of Physiology and Pharmacology, University of Bristol, Bristol BS8 1TD, United Kingdom.
authors: Graham
authors: http://orcid.org/0000-0002-9572-5359
authors: G
authors: Collingridge
authors: Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.
authors: Stéphane
authors: S
authors: Auvin
authors: Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France.
authors: Pierre
authors: http://orcid.org/0000-0002-0909-4221
authors: P
authors: Gressens
authors: Department of Pharmaceutical Chemistry and Drug Analysis, Center for Neurosciences, Vrije Universiteit Brussel, 1090 Brussels, Belgium.
authors: Ilse
authors: I
authors: Smolders
authors: Inserm, U1141, 75019 Paris, France, University Paris Diderot, Sorbonne Paris Cité, UMR1141, 75019 Paris, France, pascal.dournaud@inserm.fr.
authors: Pascal
authors: P
authors: Dournaud
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D010122:Cystinyl Aminopeptidase / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D008032:Limbic System / Q000378:metabolism; D008297:Male; D051379:Mice; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D017481:Receptors, Somatostatin / Q000378:metabolism*; D012640:Seizures / Q000378:metabolism* / Q000517:prevention & control*
chemical_list: D017481:Receptors, Somatostatin; C106140:somatostatin receptor sst2A; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase
keywords: GPCR; insulin-regulated aminopeptidase; limbic seizures; neuropeptide; somatostatin; traffic