Universites Of Montpellier 1 And 2

Montpellier, France

Universites Of Montpellier 1 And 2

Montpellier, France
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Faucherre A.,French National Center for Scientific Research | Faucherre A.,French Institute of Health and Medical Research | Faucherre A.,Universites Of Montpellier 1 And 2 | Nargeot J.,French National Center for Scientific Research | And 8 more authors.
Journal of Neuroscience | Year: 2013

The sense of touch allows an organism to detect and respond to physical environmental stimuli. Mechanosensitive proteins play a crucial role in this process by converting the mechanical cue into a biological response. Recently, the Piezo family of stretch-activated ion channels has been identified as genuine mechanosensitive proteins. We set out to determine whether any of these genes are involved in touch response during zebrafish development. In situ hybridization indicates that piezo2b is specifically expressed in a subset of neurons (Rohon-Beard cells) responsible for detecting light touch. Using morpholino-mediated knockdown, we specifically targeted piezo2b and determined that it is involved in mediating touch-evoked response. © 2013 the authors.

Pradhan A.A.,University of California at Los Angeles | Pradhan A.A.,University of Illinois at Chicago | Perroy J.,French National Center for Scientific Research | Perroy J.,French Institute of Health and Medical Research | And 8 more authors.
Journal of Neuroscience | Year: 2016

Ligand-specific recruitment of arrestins facilitates functional selectivity of G-protein-coupled receptor signaling. Here, we describe agonist-selective recruitment of different arrestin isoforms to the delta opioid receptor inmice. Ahigh-internalizing delta opioid receptor agonist (SNC80) preferentially recruited arrestin 2 and, in arrestin 2 knock-outs (KOs), we observed a significant increase in the potency of SNC80 to inhibit mechanical hyperalgesia and decreased acute tolerance. In contrast, the low-internalizing delta agonists (ARM390, JNJ20788560) preferentially recruited arrestin 3 with unaltered behavioral effects in arrestin 2 KOs. Surprisingly, arrestin 3 KO revealed an acute tolerance to these low-internalizing agonists, an effect never observed in wild-type animals. Furthermore, we examined delta opioid receptor–Ca2+ channel coupling in dorsal root ganglia desensitized by ARM390 and the rate of resensitization was correspondingly decreased in arrestin 3 KOs. Live-cell imaging in HEK293 cells revealed that delta opioid receptors are in pre-engaged complexes with arrestin 3 at the cell membrane and that ARM390 strengthens this membrane interaction. The disruption of these complexes in arrestin 3 KOs likely accounts for the altered responses to low-internalizing agonists. Together, our results show agonist-selective recruitment of arrestin isoforms and reveal a novel endogenous role of arrestin 3 as a facilitator of resensitization and an inhibitor of tolerance mechanisms. © 2016 the authors.

Doumazane E.,French National Center for Scientific Research | Doumazane E.,Institute National Of La Sante | Doumazane E.,Universites Of Montpellier 1 And 2 | Scholler P.,French National Center for Scientific Research | And 13 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2013

In multimeric cell-surface receptors, the conformational changes of the extracellular ligand-binding domains (ECDs) associated with receptor activation remain largely unknown. This is the case for the dimeric metabotropic glutamate receptors even though a number of ECD structures have been solved. Here, using an innovative approach based on cell-surface labeling and FRET, we demonstrate that a reorientation of the ECDs is associated with receptor and G-protein activation. Our approach helps identify partial agonists and highlights allosteric interactions between the effector and binding domains. Any approach expected to stabilize the active conformation ofthe effector domain increased the agonist potency in stabilizing the active ECDs conformation. These data provide key information on the structural dynamics and drug action at metabotropic glutamate receptors and validate an approach for tackling such analysis on other receptors.

Sah R.,Howard Hughes Medical Institute | Sah R.,Boston Childrens Hospital | Sah R.,Brigham and Women's Hospital | Mesirca P.,Universites Of Montpellier 1 And 2 | And 8 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2013

Sick sinus syndrome and atrioventricular block are common clinical problems, often necessitating permanent pacemaker placement, yet the pathophysiology of these conditions remains poorly understood. Here we show that Transient Receptor Potential Melastatin 7 (TRPM7), a divalent-permeant channel-kinase of unknown function, is highly expressed in embryonic myocardium and sinoatrial node (SAN) and is required for cardiac automaticity in these specialized tissues. TRPM7 disruption in vitro, in cultured embryonic cardiomyocytes, significantly reduces spontaneous Ca2+ transient firing rates and is associated with robust down-regulation of Hcn4, Cav3.1, and SERCA2a mRNA. TRPM7 knockdown in zebrafish, global murine cardiac Trpm7 deletion (KOαMHC-Cre), and tamoxifen- inducible SAN restricted Trpm7 deletion (KOHCN4-CreERT2) disrupts cardiac automaticity in vivo. Telemetered and sedated KOαMHC-Cre and KOHCN4-CreERT2 mice show episodes of sinus pauses and atrioventricular block. Isolated SAN from KOαMHC-Cre mice exhibit diminished Ca2+ transient firing rates with a blunted diastolic increase in Ca2+. Action potential firing rates are diminished owing to slower diastolic depolarization. Accordingly, Hcn4 mRNA and the pacemaker current, If, are diminished in SAN from both KOαMHC-Cre and KOHCN4-CreERT2 mice. Moreover, heart rates of KOαMHC-Cre mice are less sensitive to the selective If blocker ivabradine and acute application of the recently identified TRPM7 blocker FTY720 has no effect on action potential firing rates of wild-type SAN cells. We conclude that TRPM7 influences diastolic membrane depolarization and automaticity in SAN indirectly via regulation of Hcn4 expression.

Baneres J.-L.,Max Mousseron Institute of Biomolecules | Baneres J.-L.,Universites Of Montpellier 1 And 2 | Popot J.-L.,CNRS Molecular Chemistry Laboratory | Popot J.-L.,University Paris Diderot | And 3 more authors.
Trends in Biotechnology | Year: 2011

G-protein-coupled receptors (GPCRs), the largest family of integral membrane proteins, participate in the regulation of many physiological functions and are the targets of approximately 30% of currently marketed drugs. However, knowledge of the structural and molecular bases of GPCR functions remains limited owing to difficulties related to their overexpression, purification and stabilization. The development of new strategies aimed at obtaining large amounts of functional GPCRs is therefore crucial. Here, we review the most recent advances in the production and functional folding of GPCRs from Escherichia coli inclusion bodies. Major breakthroughs open exciting perspectives for structural and dynamic investigations of GPCRs. In particular, combining targeting to bacterial inclusion bodies with amphipol-assisted folding is emerging as a highly powerful strategy. © 2011 Elsevier Ltd.

Meziane H.,Institute Of La Clinique Of La Souris | Schaller F.,French Institute of Health and Medical Research | Bauer S.,French Institute of Health and Medical Research | Villard C.,Plateforme Proteomique et Innovation Technologique Timone | And 6 more authors.
Biological Psychiatry | Year: 2015

Background Mutations of MAGEL2 have been reported in patients presenting with autism, and loss of MAGEL2 is also associated with Prader-Willi syndrome, a neurodevelopmental genetic disorder. This study aimed to determine the behavioral phenotype of Magel2-deficient adult mice, to characterize the central oxytocin (OT) system of these mutant mice, and to test the curative effect of a peripheral OT treatment just after birth. Methods We assessed the social and cognitive behavior of Magel2-deficient mice, analyzed the OT system of mutant mice treated or not by a postnatal administration of OT, and determined the effect of this treatment on the brain. Results Magel2 inactivation induces a deficit in social recognition and social interaction and a reduced learning ability in adult male mice. In these mice, we reveal anatomical and functional modifications of the OT system and show that these defects change from birth to adulthood. Daily administration of OT in the first postnatal week was sufficient to prevent deficits in social behavior and learning abilities in adult mutant male mice. We show that this OT treatment partly restores a normal OT system. Thus, we report that an alteration of the OT system around birth has long-term consequences on behavior and on cognition. Importantly, an acute OT treatment of Magel2-deficient pups has a curative effect. Conclusions Our study reveals that OT plays a crucial role in setting social behaviors during a period just after birth. An early OT treatment in this critical period could be a novel therapeutic approach for the treatment of neurodevelopmental disorders such as Prader-Willi syndrome and autism. © 2015 Society of Biological Psychiatry.

Dalle S.,French National Center for Scientific Research | Dalle S.,French Institute of Health and Medical Research | Dalle S.,Universites Of Montpellier 1 And 2 | Burcelin R.,French Institute of Health and Medical Research | And 2 more authors.
Cellular Signalling | Year: 2013

Type 2 diabetes occurs when the β-cells do not secrete enough insulin to counter balance insulin resistance. GLP-1 and GIP are insulinotropic peptides which are thought to benefit to β-cell physiology. On one hand sustained pharmacological levels of GLP-1 are achieved by subcutaneous administration of GLP-1 analogs while transient and lower physiological levels of GLP-1 are attained following DPP4 inhibitor (DPP4i) treatment. On the other hand, DPP4i increase GLP-1 concentration into the portal vein to recruit the gut-to brain-to pancreas axis which is not the case with injected analogs. Hence, these differences between GLP-1 analogs and DPP4i indicate that both strategies could differentially impact β-cell behavior. Here, we summarize the effects of GLP-1 analogs and DPP4i on β-cell physiology. We discuss the possibility that production of signaling molecules, such as cAMP, generated into the β-cells by native GLP-1 or pharmacological GLP-1 analogs may vary and engage different downstream signaling networks. Hence, deciphering which signaling networks are engaged following GLP-1 analogs or DPP4i administration appears to be critical to unveil the contribution of each treatment/strategy to engage β-cell cellular processes. © 2012 Elsevier Inc.

Marchi N.,Cleveland Clinic | Lerner-Natoli M.,French National Center for Scientific Research | Lerner-Natoli M.,French Institute of Health and Medical Research | Lerner-Natoli M.,Universites Of Montpellier 1 And 2
Neuroscientist | Year: 2013

The role of the blood-brain barrier (BBB) in epilepsy has evolved from an obstacle for drug brain delivery to an etiological factor contributing to seizures. Recent evidence has shown cerebrovascular angiogenesis and increased BBB permeability in the epileptic foci of patients and in experimental models of seizure. The molecular players involved in cerebrovascular remodeling in the epileptic brain are similar to those reported for other brain disorders. The question arises whether pharmacological solutions restoring a proper BBB permeability and preventing dysregulated angiogenesis could be also beneficial in mitigating seizures. We now summarize the available data supporting the role of vascular remodeling and angiogenesis in the epileptic brain, taking into account that the BBB is a multi-cellular structure, reacting to physiological and pathological stimuli. Drugs targeting aberrant angiogenesis could be beneficial in reducing seizure burden when used in combination with available anti-epileptic drugs. We also offer an overview of novel cellular players, such as pericytes, which may participate in cerebrovascular remodeling in the epileptic brain. The possible role of angiogenesis in drug-resistant forms of epilepsy associated with neurovascular dysplasia is discussed. Finally, we speculate on whether the formation of leaky BBB vessels could have an impact on the cerebrovascular rheology and on the physiological mechanisms regulating brain homeostasis. © The Author(s) 2012.

Jopling C.,Universites Of Montpellier 1 And 2 | Belmonte J.C.I.,Salk Institute for Biological Studies
Cell Cycle | Year: 2012

Although adult mammals are unable to significantly regenerate their heart, this is not the case for a number of other vertebrate species. In particular, zebrafish are able to fully regenerate their heart following amputation of up to 20% of the ventricle. Soon after amputation, cardiomyocytes dedifferentiate and proliferate to regenerate the missing tissue. More recently, identical results have also been obtained in neonatal mice. Ventricular amputation of neonates leads to a robust regenerative response driven by the proliferation of existing cardiomyocytes in a similar manner to zebrafish. However, this ability is progressively lost during the first week of birth. The fact that adult zebrafish retain the capacity to regenerate their heart suggests that they either possess a unique regenerative mechanism, or that adult mammals lose/ inhibit this process. p38α MAPK has previously been shown to negatively regulate the proliferation of adult mammalian cardiomyocytes. We sought to determine whether a similar mechanism exists in adult zebrafish, and whether this needs to be overcome to allow regeneration to proceed. To determine whether p38α MAPK also regulates zebrafish cardiomyocytes in a similar manner, we generated conditional transgenic zebrafish in which either dominant-negative or active p38α MAPK are specifically expressed in cardiomyocytes. We found that active p38α MAPK but not dominant-negative p38α MAPK blocks proliferation of adult zebrafish cardiomyocytes and, consequently, heart regeneration as well. It appears that adult zebrafish cardiomyocytes share many characteristics with adult mammalian cardiomyocytes, including p38α MAPK-mediated cell cycle inhibition. These findings raise the possibility that zebrafish-like heart regeneration could be achieved in adult mammals. © 2012 Landes Bioscience.

Mollard P.,French National Center for Scientific Research | Mollard P.,French Institute of Health and Medical Research | Mollard P.,Universites Of Montpellier 1 And 2 | Hodson D.J.,French National Center for Scientific Research | And 8 more authors.
Trends in Endocrinology and Metabolism | Year: 2012

Recent advances in tridimensional (3D) tissue imaging have considerably enriched our view of the pituitary gland and its development. Whereas traditional histology of the pituitary anterior lobe portrayed this tissue as a patchwork of cells, 3D imaging revealed that cells of each lineage form extensive and structured homotypic networks. In the adult gland these networks contribute to the robustness and coordination of the cell response to secretagogs. In addition, the network organization adapts to changes in endocrine environment, as revealed by the sexually dimorphic growth hormone (GH) cell network. Further work is required to establish better the molecular basis for homotypic and heterotypic interactions in the pituitary as well as the implications of these interactions for pituitary function and dysfunction in humans. © 2012 Elsevier Ltd.

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