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23 results on '"Institut de pharmacologie moléculaire et cellulaire ( IPMC )"'

1. Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype

Author

Catherine Heurteaux, Nicolas Guy, Malika El Yacoubi, Susanne Thümmler, Guillaume Lucas, Jean-Marie Vaugeois, Nicolas Blondeau, Marc Borsotto, Guy Debonnel, Xiao-Dong Peng, Gabriella Gobbi, Michel Lazdunski, Catherine Widmann, Florence Noble, Institut de pharmacologie moléculaire et cellulaire ( IPMC ), Université Nice Sophia Antipolis ( UNS ), Université Côte d'Azur ( UCA ) -Université Côte d'Azur ( UCA ) -Centre National de la Recherche Scientifique ( CNRS ), Child Psychiatry, McGill University, Neuropsycho-pharmacologie expérimentale, Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Centre National de la Recherche Scientifique ( CNRS ), Pharmacochimie moléculaire et structurale, Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), McGill University = Université McGill [Montréal, Canada], Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Serotonin, medicine.medical_specialty, Genotype, Drug Resistance, Pharmacology, Biology, Neurotransmission, Synaptic Transmission, Mice, 03 medical and health sciences, chemistry.chemical_compound, Potassium Channels, Tandem Pore Domain, 0302 clinical medicine, Corticosterone, Fluoxetine, Internal medicine, medicine, Animals, Neurotransmitter, Depression (differential diagnoses), 030304 developmental biology, Mice, Knockout, Analysis of Variance, Depressive Disorder, 0303 health sciences, Behavior, Animal, Pyramidal Cells, General Neuroscience, Antidepressive Agents, Potassium channel, 3. Good health, Phenotype, Endocrinology, chemistry, Antidepressant, Gene Deletion, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery, medicine.drug
Abstract

Depression is a devastating illness with a lifetime prevalence of up to 20%. The neurotransmitter serotonin or 5-hydroxytryptamine (5-HT) is involved in the pathophysiology of depression and in the effects of antidepressant treatments. However, molecular alterations that underlie the pathology or treatment of depression are still poorly understood. The TREK-1 protein is a background K+ channel regulated by various neurotransmitters including 5-HT. In mice, the deletion of its gene (Kcnk2, also called TREK-1) led to animals with an increased efficacy of 5-HT neurotransmission and a resistance to depression in five different models and a substantially reduced elevation of corticosterone levels under stress. TREK-1–deficient (Kcnk2−/−) mice showed behavior similar to that of naive animals treated with classical antidepressants such as fluoxetine. Our results indicate that alterations in the functioning, regulation or both of the TREK-1 channel may alter mood, and that this particular K+ channel may be a potential target for new antidepressants.

Published
2006
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2. Idealized multiple-timescale model of cortical spreading depolarization initiation and pre-epileptic hyperexcitability caused by NaV1.1/SCN1A mutations

Author

Louisiane Lemaire, Mathieu Desroches, Martin Krupa, Massimo Mantegazza, Mathématiques pour les Neurosciences (MATHNEURO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Bernstein Center for Computational Neuroscience [Berlin], Humboldt University Of Berlin, Laboratoire Jean Alexandre Dieudonné (LJAD), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut de pharmacologie moléculaire et cellulaire (IPMC), and Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Applied Mathematics, Modeling and Simulation, [MATH.MATH-DS]Mathematics [math]/Dynamical Systems [math.DS], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Agricultural and Biological Sciences (miscellaneous)
Abstract

NaV1.1 (SCN1A) is a voltage-gated sodium channel mainly expressed in GABAergic neurons. Loss of function mutations of NaV1.1 lead to epileptic disorders, while gain of function mutations cause a migraine in which cortical spreading depolarizations (CSDs) are involved. It is still debated how these opposite effects initiate two different manifestations of neuronal hyperactivity: epileptic seizures and CSD. To investigate this question, we previously built a conductance-based model of two neurons (GABAergic and pyramidal), with dynamic ion concentrations (Lemaire et al. in PLOS Comput. Biol. 17(7):e1009239, 2021). When implementing either NaV1.1 migraine or epileptogenic mutations, ion concentration modifications acted as slow processes driving the system to the corresponding pathological firing regime. However, the large dimensionality of the model complicated the exploitation of its implicit multi-timescale structure. Here, we substantially simplify our biophysical model to a minimal version more suitable for bifurcation analysis. The explicit timescale separation allows us to apply slow-fast theory, where slow variables are treated as parameters in the fast singular limit. In this setting, we reproduce both pathological transitions as dynamic bifurcations in the full system. In the epilepsy condition, we shift the spike-terminating bifurcation to lower inputs for the GABAergic neuron, to model an increased susceptibility to depolarization block. The resulting failure of synaptic inhibition triggers hyperactivity of the pyramidal neuron. In the migraine scenario, spiking-induced release of potassium leads to the abrupt increase of the extracellular potassium concentration. This causes a dynamic spike-terminating bifurcation of both neurons, which we interpret as CSD initiation.

Published
2023
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3. Nanoscale architecture of a VAP-A-OSBP tethering complex at membrane contact sites

Author

Joëlle Bigay, Aurélie Di Cicco, Eugenio de la Mora, Bruno Mesmin, Daniel Lévy, Bruno Antonny, John Manzi, Romain Gautier, Joël Polidori, Manuela Dezi, Daniel Castaño-Díez, Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), and University of Basel (Unibas)

Subjects
0301 basic medicine, Science, General Physics and Astronomy, behavioral disciplines and activities, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Organelle, OSBP, Multidisciplinary, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Chemistry, Endoplasmic reticulum, General Chemistry, Golgi apparatus, Small molecule, humanities, Transmembrane protein, 030104 developmental biology, Membrane, symbols, Biophysics, Cryoelectron tomography, Plant lipid transfer proteins, 030217 neurology & neurosurgery
Abstract

Membrane contact sites (MCS) are subcellular regions where two organelles appose their membranes to exchange small molecules, including lipids. Structural information on how proteins form MCS is scarce. We designed an in vitro MCS with two membranes and a pair of tethering proteins suitable for cryo-tomography analysis. It includes VAP-A, an ER transmembrane protein interacting with a myriad of cytosolic proteins, and oxysterol-binding protein (OSBP), a lipid transfer protein that transports cholesterol from the ER to the trans Golgi network. We show that VAP-A is a highly flexible protein, allowing formation of MCS of variable intermembrane distance. The tethering part of OSBP contains a central, dimeric, and helical T-shape region. We propose that the molecular flexibility of VAP-A enables the recruitment of partners of different sizes within MCS of adjustable thickness, whereas the T geometry of the OSBP dimer facilitates the movement of the two lipid-transfer domains between membranes., Membrane contact sites (MCS) are subcellular regions where two organelles appose their membranes to exchange small molecules, including lipids. Here authors designed an in vitro MCS suitable for cryotomography and sub-tomogram analysis which sheds light on the recruitment of proteins of different sizes within MCS of adjustable thickness.

Published
2021
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4. Inhibition of eIF5A hypusination reprogrammes metabolism and glucose handling in mouse kidney

Author

Marc Cougnon, Karine Dumas, Christophe Duranton, Nicolas Soubeiran, Catherine Pons, Isabelle Rubera, Didier F. Pisani, Luc Pellerin, Sébastien Giraud, Thierry Hauet, Romain Carcy, Marina Shkreli, Jean-François Tanti, Nicolas Blondeau, Nicolas Melis, Michel Tauc, Laboratoire de PhysioMédecine Moléculaire (LP2M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Hôpital Pasteur [Nice] (CHU), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Centre méditerranéen de médecine moléculaire (C3M), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Ischémie Reperfusion en Transplantation d’Organes Mécanismes et Innovations Thérapeutiques ( IRTOMIT), Université de Poitiers-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), ANR-19-CE18-0029,KIRI,Ciblage de l'agression ischémique, application à la transplantation d'organes(2019), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Pisani, Didier, and Ciblage de l'agression ischémique, application à la transplantation d'organes - - KIRI2019 - ANR-19-CE18-0029 - AAPG2019 - VALID

Subjects
Male, Cancer Research, Physiology, Immunology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Oxidative phosphorylation, Kidney, Article, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Peptide Initiation Factors, medicine, Animals, lcsh:QH573-671, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, 030304 developmental biology, 0303 health sciences, biology, lcsh:Cytology, Chemistry, Glucose transporter, RNA-Binding Proteins, Cell Biology, Metabolism, Cell biology, Renal glucose reabsorption, Glucose, medicine.anatomical_structure, Anaerobic glycolysis, Renal physiology, biology.protein, GLUT1, 030217 neurology & neurosurgery
Abstract

Inhibition of the eukaryotic initiation factor 5A activation by the spermidine analogue GC7 has been shown to protect proximal cells and whole kidneys against an acute episode of ischaemia. The highlighted mechanism involves a metabolic switch from oxidative phosphorylation toward glycolysis allowing cells to be transiently independent of oxygen supply. Here we show that GC7 decreases protein expression of the renal GLUT1 glucose transporter leading to a decrease in transcellular glucose flux. At the same time, GC7 modifies the native energy source of the proximal cells from glutamine toward glucose use. Thus, GC7 acutely and reversibly reprogrammes function and metabolism of kidney cells to make glucose its single substrate, and thus allowing cells to be oxygen independent through anaerobic glycolysis. The physiological consequences are an increase in the renal excretion of glucose and lactate reflecting a decrease in glucose reabsorption and an increased glycolysis. Such a reversible reprogramming of glucose handling and oxygen dependence of kidney cells by GC7 represents a pharmacological opportunity in ischaemic as well as hyperglycaemia-associated pathologies from renal origin.

Published
2021
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5. Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer’s disease-like pathologies and cognitive deficits

Author

Alain Lacampagne, Andrew R. Marks, Steven Reiken, Clark A. Briggs, Xiaoping Liu, Ottavio Arancio, Andrew F. Teich, Shreaya Chakroborty, Charlotte Bauer, Michael L. Shelanski, Nathalie Saint, Inger Lauritzen, Fabrice Duprat, Grace E. Stutzmann, Mounia Chami, Frédéric Checler, Ran Zalk, Renaud Bussiere, Albano C. Meli, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Columbia University [New York], Department of Physiology & Cellular Biophysics, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Chicago Medical School [Rosalind Franklin University], Rosalind Franklin University, Department of Neuroscience Rosalind Franklin University, Rosalind Franklin University-Chicago Medical Scchool, Università degli Studi di Ferrara (UniFE), and Columbia University College of Physicians and Surgeons

Subjects
Male, 0301 basic medicine, [SDV]Life Sciences [q-bio], Ryanodine receptor 2, Mice, 0302 clinical medicine, Phosphorylation, ComputingMilieux_MISCELLANEOUS, biology, Ryanodine receptor, Nitrosylation, PKA-dependent phosphorylation, musculoskeletal system, Sarcoplasmic Reticulum, cardiovascular system, Female, Alzheimer's disease, Signal transduction, tissues, medicine.medical_specialty, Amyloid beta, Mice, Transgenic, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Alzheimer Disease, Internal medicine, medicine, Animals, Humans, Calcium Signaling, Maze Learning, Endoplasmic reticulum, Recognition, Psychology, Ryanodine Receptor Calcium Release Channel, medicine.disease, Cyclic AMP-Dependent Protein Kinases, 030104 developmental biology, Endocrinology, Oxidative stress, Synaptic plasticity, biology.protein, Calcium, Neurology (clinical), Cognition Disorders, Protein Processing, Post-Translational, Neuroscience, 030217 neurology & neurosurgery
Abstract

The mechanisms underlying ryanodine receptor (RyR) dysfunction associated with Alzheimer disease (AD) are still not well understood. Here, we show that neuronal RyR2 channels undergo post-translational remodeling (PKA phosphorylation, oxidation, and nitrosylation) in brains of AD patients, and in two murine models of AD (3 × Tg-AD, APP +/− /PS1 +/−). RyR2 is depleted of calstabin2 (KFBP12.6) in the channel complex, resulting in endoplasmic reticular (ER) calcium (Ca2+) leak. RyR-mediated ER Ca2+ leak activates Ca2+-dependent signaling pathways, contributing to AD pathogenesis. Pharmacological (using a novel RyR stabilizing drug Rycal) or genetic rescue of the RyR2-mediated intracellular Ca2+ leak improved synaptic plasticity, normalized behavioral and cognitive functions and reduced Aβ load. Genetically altered mice with congenitally leaky RyR2 exhibited premature and severe defects in synaptic plasticity, behavior and cognitive function. These data provide a mechanism underlying leaky RyR2 channels, which could be considered as potential AD therapeutic targets.

Published
2017
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6. Time course of fluid responsiveness in sepsis: the fluid challenge revisiting (FCREV) study

Author

Claire, Roger, Laurent, Zieleskiewicz, Christophe, Demattei, Karim, Lakhal, Gael, Piton, Benjamin, Louart, Jean-Michel, Constantin, Russell, Chabanne, Jean-Sébastien, Faure, Yazine, Mahjoub, Isabelle, Desmeulles, Hervé, Quintard, Jean-Yves, Lefrant, Laurent, Muller, Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Service Anesthésie et Réanimation [Hôpital Nord - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Aide à la Décision pour une Médecine Personnalisé - Laboratoire de Biostatistique, Epidémiologie et Recherche Clinique - EA 2415 (AIDMP), Université Montpellier 1 (UM1)-Université de Montpellier (UM), Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Service de gastro-entérologie, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Caractéristiques féminines des dysfonctions des interfaces cardio-vasculaires (EA 2992), Service d'Anésthésie Réanimation [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, CHU Clermont-Ferrand, Service de dermatologie [CHU d'Amiens-Picardie], CHU Amiens-Picardie, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Prémilleux, Annick, Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), and Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, Time Factors, [SDV]Life Sciences [q-bio], Fluid responsiveness, Hemodynamics, Critical Care and Intensive Care Medicine, law.invention, 0302 clinical medicine, 030202 anesthesiology, law, Prospective Studies, Cardiac Output, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, lcsh:Medical emergencies. Critical care. Intensive care. First aid, Shock, Stroke volume, Middle Aged, Intensive care unit, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, [SDV] Life Sciences [q-bio], Intensive Care Units, Editorial Commentary, Echocardiography, Anesthesia, Shock (circulatory), Female, SOFA score, France, medicine.symptom, Subgroup analysis, Sepsis, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, medicine, Humans, Arterial Pressure, Fluid challenge, Aged, business.industry, Septic shock, 030208 emergency & critical care medicine, lcsh:RC86-88.9, Crystalloid Solutions, medicine.disease, 13. Climate action, ICU, Fluid Therapy, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Fluid challenge (FC) is one of the most common practices in Intensive Care Unit (ICU). The present study aimed to evaluate whether echocardiographic assessment of the response to FC at the end of the infusion or 20 min later could affect the results of the FC. This is a prospective, observational, multicenter study including all ICU patients in septic shock requiring a FC of 500 mL crystalloids over 10 min. Fluid responsiveness was defined as a > 15% increase in stroke volume (SV) assessed by velocity-time integral (VTI) measurements at baseline (T0), at the end of FC (T10), then 10 (T20) and 20 min (T30) after the end of FC. From May 20, 2014, to January 7, 2016, a total of 143 patients were enrolled in 11 French ICUs (mean age 64 ± 14 years, median IGS II 53 [43–63], median SOFA score 10 [8–12]). Among the 76/143 (53%) patient responders to FC at T10, 37 patients were transient responders (TR), i.e., became non-responders (NR) at T30 (49%, 95%CI = [37–60]), and 39 (51%, 95%CI = [38–62]) patients were persistent responders (PR), i.e., remained responders at T30. Among the 67 NR at T10, 4 became responders at T30, (6%, 95%CI = [1.9–15.3]). In the subgroup analysis, no statistical difference in hemodynamic and echocardiographic parameters was found between groups. This study shows that 51.3% of initial responders have a persistent response to fluid 30 min after the beginning of fluid infusion and only 41.3% have a transient response highlighting that fluid responsiveness is time dependent. ClinicalTrials.gov , NCT02116413 . Registered on April 16, 2014

Published
2019
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7. η-Secretase processing of APP inhibits neuronal activity in the hippocampus

Author

Scherazad Kootar, Marc Aurel Busche, Steven Moore, Lewis D. B. Evans, Sabina Tahirovic, Daniel Hornburg, Dietmar Rudolf Thal, Anna Daria, Hélène Marie, Jochen Herms, Frederick J. Livesey, Christian Haass, Elisabeth Kremmer, Vilmantas Giedraitis, Felix Meissner, Heike Hampel, Veronika Müller, Ulrike Müller, Michael Willem, Camilla Giudici, Saak V. Ovsepian, Michael T. Heneka, Brigitte Nuscher, Lars Lannfelt, Andrea Wenninger-Weinzierl, Arthur Konnerth, Magda Chafai, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Equipe de Recherche en Syntaxe et Sémantique (ERSS), Université Toulouse - Jean Jaurès (UT2J)-Université Bordeaux Montaigne-Centre National de la Recherche Scientifique (CNRS), European IPF Registry and Biobank (eurIPFreg/bank), Institut für Molekulare Immunologie, GSF, German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, Department of Experimental Systems Immunology [Martinsried, Allemagne], Max Planck Institute of Biochemistry (MPIB), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Ludwig-Maximilians-Universität München (LMU), Institute of Neuroscience and Center for Integrated Protein Science, and Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)

Subjects
enzymology [Neurites], Male, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, ADAM10, Long-Term Potentiation, physiology [Hippocampus], genetics [Amyloid Precursor Protein Secretases], Plaque, Amyloid, antagonists & inhibitors [Amyloid Precursor Protein Secretases], Molecular neuroscience, Hippocampal formation, Hippocampus, APP protein, human, ADAM10 Protein, Mice, Amyloid beta-Protein Precursor, 0302 clinical medicine, metabolism [Amyloid beta-Protein Precursor], metabolism [Peptide Fragments], Aspartic Acid Endopeptidases, Premovement neuronal activity, chemistry [Amyloid beta-Protein Precursor], ComputingMilieux_MISCELLANEOUS, Neurons, enzymology [Neurons], 0303 health sciences, Multidisciplinary, biology, metabolism [Neurites], Long-term potentiation, deficiency [Amyloid Precursor Protein Secretases], antagonists & inhibitors [Aspartic Acid Endopeptidases], metabolism [Aspartic Acid Endopeptidases], physiology [Neurons], Research Highlight, cerebrospinal fluid [Amyloid beta-Protein Precursor], Ectodomain, Biochemistry, genetics [Amyloid beta-Protein Precursor], Female, ddc:500, Single-Cell Analysis, metabolism [Alzheimer Disease], metabolism [Matrix Metalloproteinases, Membrane-Associated], Matrix Metalloproteinases, Membrane-Associated, Bace1 protein, mouse, ADAM10 protein, human, In Vitro Techniques, Article, 03 medical and health sciences, enzymology [Hippocampus], Calcium imaging, cerebrospinal fluid [Amyloid Precursor Protein Secretases], Alzheimer Disease, BACE1 protein, human, mental disorders, deficiency [Matrix Metalloproteinases, Membrane-Associated], Neurites, Animals, Humans, Calcium Signaling, deficiency [Aspartic Acid Endopeptidases], Mmp24 protein, mouse, 030304 developmental biology, enzymology [Alzheimer Disease], Membrane Proteins, metabolism [Amyloid Precursor Protein Secretases], Peptide Fragments, Molecular Weight, ADAM Proteins, Disease Models, Animal, genetics [Aspartic Acid Endopeptidases], metabolism [ADAM Proteins], cytology [Hippocampus], chemistry [Peptide Fragments], Proteolysis, biology.protein, Amyloid Precursor Protein Secretases, Protein Processing, Post-Translational, Amyloid precursor protein secretase, metabolism [Membrane Proteins], 030217 neurology & neurosurgery
Abstract

Alzheimer's disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid β-peptide (Aβ)1. Two principal physiological pathways either prevent or promote Aβ generation from its precursor (amyloid precursor protein; APP) in a competitive manner1. Modulation of the amyloidogenic pathway is currently exploited by anti-Aβ therapeutic strategies2. Although APP processing has been studied in great detail, unknown proteolytic events appear to hinder stoichiometric analyses of APP metabolism in vivo3. We now identified higher molecular weight C-terminal fragments of APP (CTF-η) in addition to the long-known α- and β-secretase (a disintegrin and metalloproteinase; ADAM10 and β-site APP cleaving enzyme 1; BACE1) generated CTF-α and CTF-β. Generation of CTF-η is mediated in part by membrane bound matrix-metalloproteinases such as MT5-MMP, referred to as η-secretase activity. η-Secretase cleavage occurs primarily at amino acids 504/505 of APP(695) releasing a truncated, soluble APP ectodomain (sAPP-η). Upon shedding of sAPP-η CTF-η is further processed by ADAM10 and BACE1 to release long and short Aη peptides (Aη-α and Aη-β). Aη peptides are therefore distinct from N-terminally extended Aβ variants4,5, since they do not extend to the γ-secretase cleavage sites. η-Secretase produced CTFs are enriched in dystrophic neurites in an AD mouse model and human AD brains6. Genetic and pharmacological inhibition of BACE1 activity results in a robust accumulation of CTF-η and Aη-α. In mice treated with a potent BACE1 inhibitor hippocampal long-term potentiation (LTP) was reduced. Strikingly, when recombinant or synthetic Aη-α was applied on hippocampal slices ex vivo, LTP was lowered. Furthermore, in vivo single cell two-photon calcium imaging revealed that hippocampal neuronal activity was attenuated by Aη-α. These findings not only demonstrate a major physiologically relevant APP processing pathway but may also suggest potential translational relevance for therapeutic strategies targeting APP processing.

Published
2015
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8. Robust estimation of the motile cilia beating frequency

Author

Olivier Meste, Alice Guyon, Frédéric Brau, Laboratoire d'Informatique, Signaux, et Systèmes de Sophia-Antipolis (I3S) / Equipe SIGNAL, Signal, Images et Systèmes (Laboratoire I3S - SIS), Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Laboratoire d'Informatique, Signaux, et Systèmes de Sophia Antipolis (I3S), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
Male, Ependymal Cell, Computer science, brain, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Computation, Cytological Techniques, Biomedical Engineering, Frequency Estimation, Mice, symbols.namesake, Grid pattern, Robustness (computer science), Ependyma, Animals, Cilia, Signal processing, Pixel, Signal Processing, Computer-Assisted, Computer Science Applications, Mice, Inbred C57BL, Fourier transform, Signal Processing, Motile cilium, symbols, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Artifacts, Biological system, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Biomedical engineering
Abstract

International audience; The estimation of the cilia beating frequency (CBF) is of great interest in understanding how the CBF modulates liquid fluxes and how it is controlled by the ciliated cell intra- and/or extra-cellular medium composition in physiological processes. Motion artifacts and camera defaults may hinder the computation of the frequency variations during long lasting experiments.We have developed a new analysis approach consisting of a preliminary corrective step (removal of a grid pattern on the image sequence and shift compensation), followed by a harmonic model of the observed cilia using a Maximum Likelihood Estimator framework. It is shown that a more accurate estimation of the frequency can be obtained by averaging the squared Fourier transform of individual pixels followed by a particular summation over the different frequencies, namely the Compressed Spectrum. Robustness of the proposed method over traditional approaches is shown by several examples and simulations. The method is then applied to images of samples containing ciliated ependymal cells located in the third cerebral ventricle of mouse brains, showing that even small variations in CBF in response to changes in the amount of oxygenation, pH or glucose were clearly visible in the computed frequencies. As a conclusion, this method reveals a fine metabolic tuning of the cilia beating in ependimocytes lining the third cerebral ventricle. Such regulations are likely to participate in homeostatic mechanisms regulating CSF movements and brain energy supply.

Published
2015
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9. Computational and biophysical approaches to protein–protein interaction inhibition of Plasmodium falciparum AMA1/RON2 complex

Author

Roberto F. Delgadillo, Maryse Lebrun, Martine Pugnière, Michelle L. Tonkin, Dominique Douguet, Martin J. Boulanger, Emilie Pihan, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), University of Victoria [Canada] (UVIC), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Dynamique des interactions membranaires normales et pathologiques (DIMNP), and Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Molecular Sequence Data, Biophysics, Drug Evaluation, Preclinical, Protozoan Proteins, Druggability, Antigens, Protozoan, Fluorescence Polarization, Receptors, Cell Surface, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Biology, Molecular Docking Simulation, Workflow, Protein–protein interaction, Small Molecule Libraries, Antimalarials, Inhibitory Concentration 50, Drug Discovery, Amino Acid Sequence, Physical and Theoretical Chemistry, Apical membrane antigen 1, Peptide sequence, ComputingMilieux_MISCELLANEOUS, Virtual screening, Membrane Proteins, Reproducibility of Results, Plasmodium falciparum, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Surface Plasmon Resonance, biology.organism_classification, 3. Good health, Computer Science Applications, Rhoptry neck, Biochemistry, Immunology, Computer-Aided Design, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], [CHIM.CHEM]Chemical Sciences/Cheminformatics
Abstract

Invasion of the red blood cell by Plasmodium falciparum parasites requires formation of an electron dense circumferential ring called the Moving Junction (MJ). The MJ is anchored by a high affinity complex of two parasite proteins: Apical Membrane Antigen 1 (PfAMA1) displayed on the surface of the parasite and Rhoptry Neck Protein 2 that is discharged from the parasite and imbedded in the membrane of the host cell. Structural studies of PfAMA1 revealed a conserved hydrophobic groove local- ized to the apical surface that coordinates RON2 and invasion inhibitory peptides. In the present work, we em- ployed computational and biophysical methods to identify competitive P. falciparum AMA1-RON2 inhibitors with the goal of exploring the 'druggability' of this attractive antimalarial target. A virtual screen followed by molecular docking with the PfAMA1 crystal structure was performed using an eight million compound collection that included commercial molecules, the ChEMBL malaria library and approved drugs. The consensus approach resulted in the selection of inhibitor candidates. We also developed a fluorescence anisotropy assay using a modified inhibitory peptide to experimentally validate the ability of the se- lected compounds to inhibit the AMA1-RON2 interaction. Among those, we identified one compound that displayed significant inhibition. This study offers interesting clues to improve the throughput and reliability of screening for new drug leads.

Published
2015
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10. Stimulation of 5-HT2C Receptors Improves Cognitive Deficits Induced by Human Tryptophan Hydroxylase 2 Loss of Function Mutation

Author

Adeline Etiévant, Francis Lemay, Stella Manta, Guy Escoffier, François S. Roman, François Y. Doré, Jean Levasseur-Moreau, Jean-Martin Beaulieu, Thomas Del’Guidice, Morgane Lemasson, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Institut cellule souche et cerveau / Stem Cell and Brain Research Institute (SBRI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie intégrative et adaptative (NIA), Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Institut cellule souche et cerveau (SBRI), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), and Institut cellule souche et cerveau (U846 Inserm - UCBL1)

Subjects
Agonist, medicine.drug_class, Perseveration, Mice, Transgenic, Reversal Learning, Motor Activity, Tryptophan Hydroxylase, Piperazines, 5-Hydroxytryptophan, Mice, Cognition, Serotonin Agents, Dopamine Uptake Inhibitors, Reward, Avoidance Learning, Receptor, Serotonin, 5-HT2C, medicine, Animals, Humans, Maze Learning, Pharmacology, TPH2, Methylphenidate, [SCCO.NEUR]Cognitive science/Neuroscience, Cognitive flexibility, Tryptophan hydroxylase, Olfactory Perception, medicine.disease, Psychiatry and Mental health, Schizophrenia, Pyrazines, Mutation, Original Article, medicine.symptom, Cognition Disorders, Psychology, Neuroscience, Serotonin 5-HT2 Receptor Agonists, medicine.drug
Abstract

International audience; Polymorphisms in the gene encoding the serotonin synthesis enzyme Tph2 have been identified in mental illnesses, including bipolar disorder, major depression, autism, schizophrenia, and ADHD. Deficits in cognitive flexibility and perseverative behaviors are shared common symptoms in these disorders. However, little is known about the impact of Tph2 gene variants on cognition. Mice expressing a human TPH2 variant (Tph2-KI) were used to investigate cognitive consequences of TPH2 loss of function and pharmacological treatments. We applied a recently developed behavioral assay, the automated H-maze, to study cognitive functions in Tph2-KI mice. This assay involves the consecutive discovery of three different rules: a delayed alternation task, a non-alternation task, and a delayed reversal task. Possible contribution of locomotion, reward, and sensory perception were also investigated. The expression of loss-of-function mutant Tph2 in mice was associated with impairments in reversal learning and cognitive flexibility, accompanied by perseverative behaviors similar to those observed in human clinical studies. Pharmacological restoration of 5-HT synthesis with 5-hydroxytryptophan or treatment with the 5-HT(2C) receptor agonist CP809.101 reduced cognitive deficits in Tph2-KI mice and abolished perseveration. In contrast, treatment with the psychostimulant methylphenidate exacerbated cognitive deficits in mutant mice. Results from this study suggest a contribution of TPH2 in the regulation of cognition. Furthermore, identification of a role for a 5-HT(2) receptor agonist as a cognition-enhancing agent in mutant mice suggests a potential avenue to explore for the personalized treatment of cognitive symptoms in humans with reduced 5-HT synthesis and TPH2 polymorphisms.

Published
2013
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11. Half-molar sodium lactate infusion to prevent intracranial hypertensive episodes in severe traumatic brain injured patients: a randomized controlled trial

Author

Gilles Francony, Jean François Payen, Jean Christophe Orban, Robin Legrand, Hubert Roth, Carole Ichai, Hervé Quintard, Xavier Leverve, Service de réanimation, Centre Hospitalier Universitaire de Nice (CHU Nice)-Hôpital St Roch, ANTE-INSERM U836, équipe 5, Neuroimagerie fonctionnelle et perfusion cérébrale, CIC - Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Anesthésie Réanimation, CHU Grenoble-Hôpital Michallon-CHU Grenoble-Hôpital Michallon, Centre Hospitalier Universitaire de Nice (CHU Nice), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Laboratoire de bioénergétique fondamentale et appliquée (LBFA), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Pôle Anesthésie Réanimation, and Centre Hospitalier Universitaire [Grenoble] (CHU)

Subjects
Adult, Male, Adolescent, Traumatic brain injury, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Critical Care and Intensive Care Medicine, law.invention, Sodium Lactate, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, Injury Severity Score, 0302 clinical medicine, Chlorides, Double-Blind Method, Randomized controlled trial, law, Osmotherapy, Sodium lactate, medicine, Humans, Prospective Studies, Infusions, Intravenous, Prospective cohort study, Saline, ComputingMilieux_MISCELLANEOUS, Aged, Intracranial pressure, business.industry, Sodium, 030208 emergency & critical care medicine, Middle Aged, medicine.disease, Body Fluids, nervous system diseases, 3. Good health, chemistry, Brain Injuries, Anesthesia, Female, Intracranial Hypertension, business, 030217 neurology & neurosurgery
Abstract

Preventive treatments of traumatic intracranial hypertension are not yet established. We aimed to compare the efficiency of half-molar sodium lactate (SL) versus saline serum solutions in preventing episodes of raised intracranial pressure (ICP) in patients with severe traumatic brain injury (TBI).This was a double-blind, randomized controlled trial including 60 patients with severe TBI requiring ICP monitoring. Patients were randomly allocated to receive a 48-h continuous infusion at 0.5 ml/kg/h of either SL (SL group) or isotonic saline solution (control group) within the first 12 h post-trauma. Serial measurements of ICP, as well as fluid, sodium, and chloride balance were performed over the 48-h study period. The primary outcome was the number of raised ICP (≥20 mmHg) requiring a specific treatment.Raised ICP episodes were reduced in the SL group as compared to the control group within the 48-h study period: 23 versus 53 episodes, respectively (p 0.05). The proportion of patients presenting raised ICP episodes was smaller in the SL group than in the saline group: 11 (36 %) versus 20 patients (66 %) (p 0.05). Cumulative 48-h fluid and chloride balances were reduced in the SL group compared to the control group (both p 0.01).A 48-h infusion of SL decreased the occurrence of raised ICP episodes in patients with severe TBI, while reducing fluid and chloride balances. These findings suggest that SL solution could be considered as an alternative treatment to prevent raised ICP following severe TBI.

Published
2013
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12. Genetic Approaches to Investigate the Role of CREB in Neuronal Plasticity and Memory

Author

Hélène Marie, Angel Barco, Instituto de Neurociencias de Alicante, Universidad Miguel Herández, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Transcription, Genetic, Protein Conformation, MESH: Neurons, MESH: Amino Acid Sequence, MESH: Gene Targeting, Animals, Genetically Modified, MESH: Protein Conformation, 0302 clinical medicine, MESH: Genetic Vectors, Transgenic mice, MESH: Animals, MESH: Neuronal Plasticity, MESH: Memory, Cyclic AMP Response Element-Binding Protein, Neuronal memory allocation, Neurons, Regulation of gene expression, 0303 health sciences, CREB, MESH: Gene Expression Regulation, Neurology, Neuronal plasticity, Gene Knockdown Techniques, Gene Targeting, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Cyclic AMP Response Element-Binding Protein, Virus-mediated expression, Genetic Vectors, Molecular Sequence Data, Neuroscience (miscellaneous), Biology, MESH: Animals, Genetically Modified, 03 medical and health sciences, Cellular and Molecular Neuroscience, Memory, CREB in cognition, Neuroplasticity, Metaplasticity, Animals, Humans, Amino Acid Sequence, Transcription factor, 030304 developmental biology, MESH: Molecular Sequence Data, MESH: Humans, MESH: Transcription, Genetic, MESH: Gene Knockdown Techniques, Gene Expression Regulation, Synaptic plasticity, biology.protein, Neuroscience, 030217 neurology & neurosurgery
Abstract

In neurons, the convergence of multiple intracellular signaling cascades leading to cAMP-responsive elementbinding protein (CREB) activation suggests that this transcription factor plays a critical role in integrating different inputs and mediating appropriate neuronal responses. The nature of this transcriptional response depends on both the type and strength of the stimulus and the cellular context. CREB-dependent gene expression has been involved in many different aspects of nervous system function, from embryonic development to neuronal survival, and synaptic, structural, and intrinsic plasticity. Here, we first review the different methodological approaches used to genetically manipulate CREB activity and levels in neurons in vivo in the adult brain, including recombinant viral vectors, mouse transgenesis, and gene-targeting techniques.We then discuss the impact of these approaches on our understanding of CREB’s roles in neuronal plasticity and memory in rodents. Studies combining these genetic approaches with electrophysiology and behavior provide strong evidence that CREB is critically involved in the regulation of synaptic plasticity, intrinsic excitability, and long-term memory formation. These findings pave the way for the development of novel therapeutic strategies to treat memory disorders., This research was supported by grants from the Spanish Ministry of Science and Innovation BFU2008-00611 (A.B.), CSD2007-00023 (A.B.), and SAF2008-03194-E (part of the coordinated ERA-Net NEURON project Epitherapy) (A.B.); ATIP grant (CNRS) (H.M.); and the French Foundation Plan Alzheimer (H.M.).

Published
2011
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13. Mechanisms of NK cell activation: CD4+ T cells enter the scene

Author

Claire Germain, Carmelo Luci, Franck Bihl, Veronique M. Braud, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Faculté de Médecine Pasteur, and Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Interleukin-12, MESH: Killer Cells, Natural, CD4-Positive T-Lymphocytes, Antigen-Presenting Cells, Biology, Lymphocyte Activation, 03 medical and health sciences, Cellular and Molecular Neuroscience, Interleukin 21, 0302 clinical medicine, NK-92, Humans, MESH: Lymphocyte Activation, Antigen-presenting cell, Molecular Biology, 030304 developmental biology, Pharmacology, 0303 health sciences, MESH: Humans, Lymphokine-activated killer cell, MESH: Antigen-Presenting Cells, IL-2, Janus kinase 3, MESH: CD4-Positive T-Lymphocytes, NK receptors, MESH: Interleukin-2, Cell Biology, Natural killer T cell, Interleukin-12, CD4+ T cells, Cell biology, Killer Cells, Natural, IL-12, Myeloid-derived Suppressor Cell, Interleukin 12, Natural killer cells, [SDV.IMM]Life Sciences [q-bio]/Immunology, Interleukin-2, Molecular Medicine, 030215 immunology
Abstract

International audience; Natural killer (NK) cells are innate lymphocytes involved in immunosurveillance through their cytotoxic activity and their capacity to secrete inflammatory cytokines. NK cell activation is necessary to initiate effector functions and results from a complex series of molecular and cellular events. We review here the signals that trigger NK cells and discuss recent findings showing that, besides antigen-presenting cells, T cells can play a central role in the initiation of NK cell activation in lymph nodes.

Published
2011
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14. A kinase cascade leading to Rab11-FIP5 controls transcytosis of the polymeric immunoglobulin receptor

Author

Scott M. Ulrich, Frédéric Luton, Kirk C. Hansen, Keith E. Mostov, Alma L. Burlingame, David M. Bryant, Dennis J. Eastburn, Tao Su, Marcel Verges, Kevan M. Shokat, Anirban Datta, Department of Anatomy, University of California [San Francisco] (UCSF), University of California-University of California, Department of Biochemistry and Biophysics, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Cardiovascular Genetics Centre (IdIBGi), Universitat de Girona (UdG), Department of Cellular and Molecular Pharmacology [San Francisco] (CMP), Department of Chemistry, Ithaca College, Department of Pharmaceutical Chemistry, Proteomics Core, and University of Colorado Anschutz [Aurora]

Subjects
MESH: Signal Transduction, MAPK/ERK pathway, MESH: Receptors, Polymeric Immunoglobulin, MESH: Transcytosis, MESH: Proto-Oncogene Proteins c-yes, MESH: Amino Acid Sequence, Mice, 0302 clinical medicine, MESH: Animals, Proto-Oncogene Proteins c-yes, 0303 health sciences, Receptors, Polymeric Immunoglobulin, Cell biology, ErbB Receptors, Liver, Transcytosis, Phosphorylation, Signal transduction, Signal Transduction, MESH: Rats, Endosome, Molecular Sequence Data, MESH: Sequence Alignment, MESH: Receptor, Epidermal Growth Factor, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Endosomes, Biology, Article, 03 medical and health sciences, Animals, Humans, MESH: Immunoglobulin A, Amino Acid Sequence, Protein kinase A, MESH: Mice, MESH: Protein Kinases, 030304 developmental biology, MESH: Humans, MESH: Molecular Sequence Data, Cell Biology, Immunoglobulin A, Rats, MESH: rab GTP-Binding Proteins, MESH: Endosomes, rab GTP-Binding Proteins, Polymeric immunoglobulin receptor, Protein Kinases, Sequence Alignment, RAB11A, 030217 neurology & neurosurgery, MESH: Liver
Abstract

International audience; Polymeric immunoglobulin A (pIgA) transcytosis, mediated by the polymeric immunoglobulin receptor (pIgR), is a central component of mucosal immunity and a model for regulation of polarized epithelial membrane traffic. Binding of pIgA to pIgR stimulates transcytosis in a process requiring Yes, a Src family tyrosine kinase (SFK). We show that Yes directly phosphorylates EGF receptor (EGFR) on liver endosomes. Injection of pIgA into rats induced EGFR phosphorylation. Similarly, in MDCK cells, pIgA treatment significantly increased phosphorylation of EGFR on various sites, subsequently activating extracellular signal-regulated protein kinase (ERK). Furthermore, we find that the Rab11 effector Rab11-FIP5 is a substrate of ERK. Knocking down Yes or Rab11-FIP5, or inhibition of the Yes-EGFR-ERK cascade, decreased pIgA-pIgR transcytosis. Finally, we demonstrate that Rab11-FIP5 phosphorylation by ERK controls Rab11a endosome distribution and pIgA-pIgR transcytosis. Our results reveal a novel Yes-EGFR-ERK-FIP5 signalling network for regulation of pIgA-pIgR transcytosis.

Published
2010
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15. Polycystins and renovascular mechanosensory transduction

Author

Amanda Patel, Eric Honoré, Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
Pathology, medicine.medical_specialty, TRPP Cation Channels, Autosomal dominant polycystic kidney disease, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, urologic and male genital diseases, Mechanotransduction, Cellular, 03 medical and health sciences, Paracrine signalling, 0302 clinical medicine, Polycystic kidney disease, medicine, Mechanotransduction, Autocrine signalling, MESH: Polycystic Kidney Diseases, 030304 developmental biology, Polycystic Kidney Diseases, 0303 health sciences, PKD1, MESH: Mechanotransduction, Cellular, urogenital system, Cilium, MESH: TRPP Cation Channels, Purinergic signalling, medicine.disease, female genital diseases and pregnancy complications, 3. Good health, Cell biology, Nephrology, 030217 neurology & neurosurgery
Abstract

International audience; Autosomal dominant polycystic kidney disease is a common disorder, affecting approximately one in 1,000 individuals. This disease is characterized by the presence of renal and extrarenal cysts, as well as by cardiovascular abnormalities, including hypertension and intracranial aneurysms. Mutations in the PKD1 gene account for 85% of cases, whereas mutations in PKD2 account for the remaining 15% of cases. Findings from the past 10 years indicate that polycystins, the products of the PKD genes, have a key role in renal and vascular mechanosensory transduction. In the primary cilium of renal, nodal, and endothelial cells, polycystins are proposed to act as flow sensors. In addition, the ratio of polycystin-1 to polycystin-2 regulates pressure sensing in arterial myocytes. In this Review, we summarize the data indicating that polycystins are key molecules in mechanotransduction. Moreover, we discuss the role of nucleotide release and autocrine and/or paracrine purinergic signaling in both fluid flow and pressure responses. Finally, we discuss the possible role of altered mechanosensory transduction in the etiology of polycystic kidney disease.

Published
2010
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16. Canonical TRP channels and mechanotransduction: from physiology to disease states

Author

Reza Sharif-Naeini, Fabrice Duprat, Eric Honoré, Amanda Patel, Delphine Bichet, Joost R. H. Folgering, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Scaffold protein, TRPP Cation Channels, Physiology, Duchenne muscular dystrophy, Clinical Biochemistry, Cardiomegaly, Mechano-electrical transduction, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Mechanotransduction, Cellular, Receptors, G-Protein-Coupled, Mechanoreceptor, TRPC6, TRPC1, 03 medical and health sciences, Transient receptor potential channel, 0302 clinical medicine, Physiology (medical), medicine, Animals, Humans, Mechanotransduction, Ion channel, TRPC Cation Channels, 030304 developmental biology, Muscle Cells, 0303 health sciences, Arteries, medicine.disease, Cytoskeletal Proteins, Stretch-activated ion channel, Transient receptor potential, Mechanosensitive channel, Neuroscience, Cation channel, 030217 neurology & neurosurgery
Abstract

International audience; Mechano-gated ion channels play a key physiological role in cardiac, arterial, and skeletal myocytes. For instance, opening of the non-selective stretch-activated cation channels in smooth muscle cells is involved in the pressure-dependent myogenic constriction of resistance arteries. These channels are also implicated in major pathologies, including cardiac hypertrophy or Duchenne muscular dystrophy. Seminal work in prokaryotes and invertebrates highlighted the role of transient receptor potential (TRP) channels in mechanosensory transduction. In mammals, recent findings have shown that the canonical TRPC1 and TRPC6 channels are key players in muscle mechanotransduction. In the present review, we will focus on the functional properties of TRPC1 and TRPC6 channels, on their mechano-gating, regulation by interacting cytoskeletal and scaffolding proteins, physiological role and implication in associated diseases.

Published
2010
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17. The mechano-gated K2P channel TREK-1

Author

Eric Honoré, Reza Sharif-Naeini, Joost H.A. Folgering, Fabrice Duprat, Alexandra Dedman, Amanda Patel, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Hydrogen-Ion Concentration, Biophysics, KcsA potassium channel, Nanotechnology, MESH: Receptors, G-Protein-Coupled, Biology, Second Messenger Systems, Receptors, G-Protein-Coupled, SK channel, Membrane Lipids, 03 medical and health sciences, Potassium Channels, Tandem Pore Domain, 0302 clinical medicine, Animals, Humans, MESH: Animals, Phospholipids, Ion channel, 030304 developmental biology, MESH: Phospholipids, 0303 health sciences, MESH: Stress, Mechanical, MESH: Humans, Voltage-gated ion channel, Inward-rectifier potassium ion channel, Temperature, MESH: Potassium Channels, Tandem Pore Domain, MESH: Fatty Acids, Unsaturated, General Medicine, Hydrogen-Ion Concentration, MESH: Ion Channel Gating, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Light-gated ion channel, MESH: Temperature, MESH: Second Messenger Systems, Fatty Acids, Unsaturated, Ligand-gated ion channel, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Mechanosensitive channels, Stress, Mechanical, MESH: Membrane Lipids, Ion Channel Gating, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract

The versatility of neuronal electrical activity is largely conditioned by the expression of different structural and functional classes of K+ channels. More than 80 genes encoding the main K+ channel alpha subunits have been identified in the human genome. Alternative splicing, heteromultimeric assembly, post-translational modification and interaction with auxiliary regulatory subunits further increase the molecular and functional diversity of K+ channels. Mammalian two-pore domain K+ channels (K(2P)) make up one class of K+ channels along with the inward rectifiers and the voltage- and/or calcium-dependent K+ channels. Each K(2P) channel subunit is made up of four transmembrane segments and two pore-forming (P) domains, which are arranged in tandem and function as either homo- or heterodimeric channels. This novel structural arrangement is associated with unusual gating properties including "background" or "leak" K+ channel activity, in which the channels show constitutive activity at rest. In this review article, we will focus on the lipid-sensitive mechano-gated K(2P) channel TREK-1 and will emphasize on the polymodal function of this "unconventional" K+ channel.

Published
2008
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18. Adaptive downregulation of a quinidine-sensitive cation conductance in renal principal cells of TWIK-1 knockout mice

Author

H. C. Taylor, G. J. Cooper, Jacques Barhanin, L. Robson, Ian D. Millar, Jonathan D. Kibble, Department of Biomedical Science, University of Sheffield [Sheffield], Medical Physiology Department, St. George's University [Grenada], Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Patch-Clamp Techniques, Physiology, Clinical Biochemistry, MESH: Mice, Knockout, MESH: Down-Regulation, Mice, MESH: Quinidine, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Animals, Epithelial polarity, Mice, Knockout, Membrane potential, 0303 health sciences, Reverse Transcriptase Polymerase Chain Reaction, [SDV.BA]Life Sciences [q-bio]/Animal biology, MESH: Potassium Channels, Tandem Pore Domain, Hyperpolarization (biology), Adaptation, Physiological, Quinidine, Potassium channel, Barium, Knockout mouse, Female, medicine.medical_specialty, Down-Regulation, In Vitro Techniques, Biology, 03 medical and health sciences, Potassium Channels, Tandem Pore Domain, Cations, Physiology (medical), Internal medicine, MESH: Patch-Clamp Techniques, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Intercalated Cell, RNA, Messenger, Patch clamp, Kidney Tubules, Collecting, MESH: Cations, MESH: Kidney Tubules, Collecting, MESH: Mice, MESH: RNA, Messenger, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Barium, Conductance, MESH: Adaptation, Physiological, MESH: Male, Endocrinology, MESH: Potassium, Potassium, Biophysics, MESH: Female, 030217 neurology & neurosurgery
Abstract

TWIK-1, a member of the two-pore domain K(+) channel family, is expressed in brain, kidney, and lung. The aim of this study was to examine the effect of loss of TWIK-1 on the renal cortical collecting duct. Ducts were isolated from wild-type and TWIK-1 knockout mice by enzyme digestion and whole-cell clamp obtained via the basolateral membrane. Current- and voltage-clamp approaches were used to examine K(+) conductances. No difference was observed between intercalated cells from wild-type or knockout ducts. In contrast, knockout principal cells were hyperpolarized compared to wild-type cells and had a reduced membrane conductance. This was a consequence of a fall in a barium-insensitive, quinidine-sensitive conductance (G (Quin)). G (Quin) demonstrated outward rectification and had a relatively low K(+) to Na(+) selectivity ratio. Loss of G (Quin) would be expected to lead to the hyperpolarization observed in knockout ducts by increasing fractional K(+) conductance and Na(+) uptake by the cell. Consistent with this hypothesis, knockout ducts had an increased diameter in comparison to wild-type ducts. These data suggest that G (Quin) contributes to the resting membrane potential in the cortical collecting duct and that a fall in G (Quin) could be an adaptive response in TWIK-1 knockout ducts.

Published
2006
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19. Human Congenital Infection With Trypanosoma cruzi Induces Phenotypic and Functional Modifications of Cord Blood NK Cells

Author

Aurélie Berthe, Yves Carlier, Faustino Torrico, Veronique M. Braud, Carine Truyens, Emmanuel Hermann, Amilcar Flores, Cristina Alonso-Vega, Lorenzo Moretta, Marisol Cordova, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)

Subjects
MESH: Interleukin-12, MESH: Membrane Glycoproteins, MESH: Interleukin-15, MESH: Down-Regulation, Granzymes, Interleukin 21, 0302 clinical medicine, Cytotoxic T cell, MESH: Animals, MESH: Serine Endopeptidases, Receptors, Immunologic, Interleukin-15, 0303 health sciences, Membrane Glycoproteins, Janus kinase 3, MESH: Infant, Newborn, Serine Endopeptidases, MESH: Antigens, CD56, Fetal Blood, Interleukin-12, CD56 Antigen, 3. Good health, Killer Cells, Natural, Phenotype, NK Cell Lectin-Like Receptor Subfamily K, Cord blood, Interleukin 12, Receptors, Natural Killer Cell, MESH: Trypanosoma cruzi, MESH: Killer Cells, Natural, MESH: Interferon Type II, Trypanosoma cruzi, Down-Regulation, Biology, MESH: Phenotype, Interferon-gamma, 03 medical and health sciences, Animals, Humans, MESH: Chagas Disease, MESH: Fetal Blood, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Chagas Disease, MESH: Receptors, Immunologic, 030304 developmental biology, MESH: Granzymes, MESH: Humans, Natural Cytotoxicity Triggering Receptor 3, Lymphokine-activated killer cell, Natural Cytotoxicity Triggering Receptor 1, Infant, Newborn, MESH: Interleukin-2, NKG2D, Granzyme B, Pediatrics, Perinatology and Child Health, Immunology, Interleukin-2, 030215 immunology
Abstract

We studied the phenotype and activity of cord blood natural killer (NK) cells in newborns congenitally infected with Trypanosoma cruzi. We found that the proportion of CD56(bright) NK cells was significantly decreased in cord blood from these newborns, suggesting they may have been recruited to secondary lymphoid organs. The remaining CD56(bright) NK cells exhibited a defective ability in the production of interferon (IFN)-gamma following in vitro activation with interleukin (IL)-12 + IL-2 or IL-12 + IL-15 cytokines, as compared with NK cells from uninfected newborns. In addition, cord blood NK cells from congenitally infected newborns stimulated with cytokines have a decreased release of granzyme B (GrB) when incubated with K562 target cells. This defect in cytotoxic effector function is associated with a reduced surface expression of activating NK receptors (NKp30, NKp46, and NKG2D) on CD56(dim) NK cells compared with uninfected newborns. These alterations of fetal NK cells from congenitally infected newborns may reflect a down-regulation of the NK cell response after an initial peak of activation and could also be the result of T. cruzi modulating the immune response.

Published
2006
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20. In vivo Characterization of Brain Morphometric and Metabolic Endophenotypes in Three Inbred Strains of Mice Using Magnetic Resonance Techniques

Author

Sylviane Confort-Gouny, Marie-France Penet, Angèle Viola, Patrick J. Cozzone, Yann Le Fur, Catherine Heurteaux, Christophe Laigle, Centre de résonance magnétique biologique et médicale (CRMBM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), and Université Nice Sophia Antipolis (1965 - 2019) (UNS)

Subjects
[SPI.OTHER]Engineering Sciences [physics]/Other, medicine.medical_specialty, Neurology, Hippocampus, Mice, Inbred Strains, Biology, Mice, 03 medical and health sciences, 0302 clinical medicine, Inbred strain, Genetic model, Genetics, medicine, Animals, Genetics (clinical), Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, 0303 health sciences, medicine.diagnostic_test, Brain, Magnetic resonance imaging, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Mice, Inbred C57BL, Metabolism, Phenotype, medicine.anatomical_structure, Schizophrenia, Endophenotype, Neuroscience, 030217 neurology & neurosurgery, Neuroanatomy
Abstract

C57BL6J, FVB/N and 129/SvJ mice are commonly used as background strains to engineer genetic models of brain pathologies and psychiatric disorders. Magnetic resonance imaging (MRI) and spectroscopy provide alternative approaches to neuroanatomy, histology and neurohistochemistry for investigating the correlation between genes and brain neuroanatomy and neurometabolism in vivo. We used these techniques to non-invasively characterize the cerebral morphologic and metabolic endophenotypes of inbred mouse strains commonly used in neurological and behavioral research. We observed a great variability in the volume of ventricles and of structures involved in cognitive function (cerebellum and hippocampus) among these strains. In addition, distinct metabolic profiles were evidenced with variable levels of N-acetylaspartate, a neuronal marker, and of choline, a compound found in membranes and myelin. Besides, significant differences in high-energy phosphates and phospholipids were detected. Our findings demonstrate the great morphologic and metabolic heterogeneity among C57BL/ 6J, FVB/N and 129/SvJ mice. They emphasize the importance of selecting the appropriate genetic background for over-expressing or silencing a gene and provide some directions for modeling symptoms that characterize psychiatric disorders such as autism, schizophrenia and depression.

Published
2006
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21. Pseudomonas aeruginosa eradicates Staphylococcus aureus by manipulating the host immunity

Author

Pierre-Régis Burgel, Isabelle Sermet-Gaudelus, Louise Jeammet, Gérard Lambeau, Lhousseine Touqui, Dominique Leduc, Michel Chignard, Laurent Guillemot, Clémence Martin, Philippe Morand, Dorota Sands, Yongzheng Wu, Erwan Pernet, Défense innée et inflammation, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellule Pasteur UPMC, Institut Pasteur [Paris] (IP)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5), Service de pneumologie [CHU Cochin], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Service de Pneumologie et d'Allergologie Pédiatriques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Régulation du transport anionique transépithélial : de la recherche fondamentale aux pathologies épithéliales (UMR_S 806), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National Research Institute of Mother and Child [Warsaw, Poland], Service de Bactériologie [CHU Cochin, AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], This study was supported by France ‘Vaincre la Mucoviscidose’ and ‘DIM Malinf-Region Ile de France’ foundation., We thank Dr R. Ramphal (University of Florida, Gainesville, FL, USA), Dr T. Msadek (Institut Pasteur, Paris), Dr E. Pearlman (Case Western Reserve University, Cleveland, OH, USA), Dr J.C. Olson (West Virginia University, Morgantown, WV, USA), Dr P. Peris (University of València, Spain), Dr M. Gelb (University of Washington, Seattle, WA, USA) for providing PA and SA strains as well as substrate for sPLA2 activity assay and RO032007A compound, Dr C. Schmitt (Hôpital Trousseau, Paris) for providing expectorations of children patients, V. Balloy and M. Nahori (Institut Pasteur, Paris) for technical assistance with intratracheal and intravenous instillation and C. Payre for helpful advices in sPLA2 analyses., Wu, Yongzheng, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)

Subjects
Cystic Fibrosis, MESH: ADP Ribose Transferases, General Physics and Astronomy, MESH: Staphylococcus aureus / physiology, medicine.disease_cause, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, Cystic fibrosis, Mice, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Child, MESH: Respiratory Mucosa, MESH: Animals, Child, ADP Ribose Transferases, MESH: Sputum / enzymology, 0303 health sciences, Multidisciplinary, MESH: Bronchi, respiratory system, 3. Good health, MESH: Young Adult, Staphylococcus aureus, Child, Preschool, Pseudomonas aeruginosa, Disease Progression, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Disease Progression, Adult, Host immunity, Adolescent, Bacterial Toxins, Guinea Pigs, Bronchi, Respiratory Mucosa, MESH: Epithelial Cells / enzymology, Biology, Group II Phospholipases A2, General Biochemistry, Genetics and Molecular Biology, MESH: Guinea Pigs, Microbiology, Young Adult, 03 medical and health sciences, MESH: Pseudomonas aeruginosa / physiology, medicine, Animals, Humans, MESH: Mice, [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, 030304 developmental biology, MESH: Adolescent, Respiratory tract diseases, MESH: Humans, MESH: Group II Phospholipases A2 / metabolism, 030306 microbiology, MESH: Child, Preschool, Sputum, Epithelial Cells, MESH: Adult, General Chemistry, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, respiratory tract diseases, MESH: Bacterial Toxins, Immunology, MESH: Cystic Fibrosis / enzymology, Bacterial infection, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Cystic Fibrosis / microbiology
Abstract

International audience; Young cystic fibrosis (CF) patients' airways are mainly colonized by Staphylococcus aureus, while Pseudomonas aeruginosa predominates in adults. However, the mechanisms behind this infection switch are unclear. Here, we show that levels of type-IIA-secreted phospholipase A2 (sPLA2-IIA, a host enzyme with bactericidal activity) increase in expectorations of CF patients in an age-dependent manner. These levels are sufficient to kill S. aureus, with marginal effects on P. aeruginosa strains. P. aeruginosa laboratory strains and isolates from CF patients induce sPLA2-IIA expression in bronchial epithelial cells from CF patients (these cells are a major source of the enzyme). In an animal model of lung infection, P. aeruginosa induces sPLA2-IIA production that favours S. aureus killing. We suggest that sPLA2-IIA induction by P. aeruginosa contributes to S. aureus eradication in CF airways. Our results indicate that a bacterium can eradicate another bacterium by manipulating the host immunity.

Published
2014
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22. LPS-hyporesponsiveness of mnd mice is associated with a mutation in Toll-like receptor 4

Author

Line Larivière, L Flaherty, Franck Bihl, Danielle Malo, Salman T. Qureshi, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Lipopolysaccharides, [SDV]Life Sciences [q-bio], Immunology, Receptors, Cell Surface, Biology, medicine.disease_cause, Frameshift mutation, Mice, 03 medical and health sciences, 0302 clinical medicine, Neuronal Ceroid-Lipofuscinoses, Genetics, medicine, Animals, Drosophila Proteins, Receptor, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), DNA Primers, 030304 developmental biology, 0303 health sciences, Toll-like receptor, Mutation, Membrane Glycoproteins, Innate immune system, Base Sequence, Toll-Like Receptors, medicine.disease, Mice, Mutant Strains, Transmembrane protein, 3. Good health, Cell biology, Mice, Inbred C57BL, Toll-Like Receptor 4, Phenotype, TLR4, Neuronal ceroid lipofuscinosis, 030215 immunology
Abstract

Toll-like receptors (Tlrs) are transmembrane proteins that have recently been shown to play a critical role in the innate immune recognition of microbial constituents. Among this family, Tlr4 is a crucial signal transducer for lipopolysaccharide (LPS), the major component of the Gram-negative bacteria outer cell membrane. In this paper, we report that C57BL/6.KB2-mnd mice, a model of neuronal ceroid lipofuscinosis, do not respond to LPS. This defect is associated with a spontaneous mutation in Tlr4 consisting of a large insertion within exon 2 predicting a frameshift mutation and a truncated protein.

Published
2001
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23. Activation of TREK-1 by morphine results in analgesia without adverse side effects

Author

Alain Eschalier, Abdelkrim Alloui, Jérôme Busserolles, Jacques Noël, Stéphane Lolignier, Marine Christin, Bruno Mazet, Michel Lazdunski, Emmanuel Deval, Patrick Delmas, Maïly Devilliers, Vanessa Pereira, Neuro-Dol - Clermont Auvergne (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Pharmacologie fondamentale et clinique de la douleur, Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Université Côte d'Azur (UCA), Centre de recherche en neurobiologie - neurophysiologie de Marseille (CRN2M), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Fondation pour la Recherche sur le Cerveau (DEQ 20130326482), the Société Française d’Etude et de Traitement de la Douleur, région Auvergne and FEDER, Fondation Hamel., ANR-11-BSV4-0022,TREK PAIN,Implication des canaux ioniques TREK dans la physiopathologie et la pharmacologie de la douleur(2011), ANR-09-MNPS-0037,VISCERALGY,Canaux ioniques : cibles du traitement de la douleur viscérale(2009), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)

Subjects
Male, Time Factors, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Receptors, Opioid, mu, General Physics and Astronomy, (+)-Naloxone, Pharmacology, Ion channels in the nervous system, Mice, 0302 clinical medicine, Drug tolerance, Opioid receptor, Chlorocebus aethiops, Medicine, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, Multidisciplinary, Morphine, Naloxone, Chronic pain, Drug Tolerance, 3. Good health, Analgesics, Opioid, COS Cells, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Respiratory Insufficiency, Signal Transduction, medicine.drug, medicine.drug_class, Analgesic, Pain, Mice, Transgenic, Mechanism of action, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Potassium Channels, Tandem Pore Domain, Medical research, Animals, Pain Management, Adverse effect, Crosses, Genetic, 030304 developmental biology, Dose-Response Relationship, Drug, business.industry, General Chemistry, medicine.disease, Mice, Inbred C57BL, Opioid, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Analgesia, business, Constipation, 030217 neurology & neurosurgery
Abstract

International audience; Morphine is the gold-standard pain reliever for severe acute or chronic pain but it also produces adverse side effects that can alter the quality of life of patients and, in some rare cases, jeopardize the vital prognosis. Morphine elicits both therapeutic and adverse effects primarily through the same m opioid receptor subtype, which makes it difficult to separate the two types of effects. Here we show that beneficial and deleterious effects of morphine are mediated through different signalling pathways downstream from m opioid receptor. We demonstrate that the TREK-1 K þ channel is a crucial contributor of morphine-induced analgesia in mice, while it is not involved in morphine-induced constipation, respiratory depression and dependence-three main adverse effects of opioid analgesic therapy. These observations suggest that direct activation of the TREK-1 K þ channel, acting downstream from the m opioid receptor, might have strong analgesic effects without opioid-like adverse effects.

Published
2013
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