Universites Of Montpellier 1 And 2

Montpellier, France

Universites Of Montpellier 1 And 2

Montpellier, France

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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.


Bidaud I.,French National Center for Scientific Research | Bidaud I.,French Institute of Health and Medical Research | Bidaud I.,Universites Of Montpellier 1 And 2 | Lory P.,French National Center for Scientific Research | And 2 more authors.
Biochimie | Year: 2011

Within the voltage-gated calcium channels (Cav channels) family, there are four genes coding for the L-type Cav channels (Cav1). The Cav1 channels underly many important physiological functions like excitation-contraction coupling, hormone secretion, neuronal excitability and gene transcription. Mutations found in the genes encoding the Cav channels define a wide variety of diseases called calcium channelopathies and all four genes coding the Cav1 channels are carrying such mutations. L-type calcium channelopathies include muscular, neurological, cardiac and vision syndromes. Among them, the Timothy syndrome (TS) is linked to missense mutations in CACNA1C, the gene that encodes the Ca v1.2 subunit. Here we review the important features of the Cav1 channelopathies. We also report on the specific properties of TS-Ca v1.2 channels, which display non-inactivating calcium current as well as higher plasma membrane expression. Overall, we conclude that both electrophysiological and surface expression properties must be investigated to better account for the functional consequences of mutations linked to calcium channelopathies. © 2011 Elsevier Masson SAS. All rights reserved.


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.


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 | Kissa K.,Montpellier University | And 9 more authors.
Haematologica | Year: 2014

Mechanosensitivity is an inherent property of virtually all cell types, allowing them to sense and respond to physical environmental stimuli. Stretch-activated ion channels represent a class of mechanosensitive proteins which allow cells to respond rapidly to changes in membrane tension; however their identity has remained elusive. The piezo genes have recently been identified as a family of stretch-activated mechanosensitive ion channels. We set out to determine the role of piezo1 during zebrafish development. Here we report that morpholino-mediated knockdown of piezo1 impairs erythrocyte survival without affecting hematopoiesis or differentiation. Our results demonstrate that piezo1 is involved in erythrocyte volume homeostasis, disruption of which results in swelling/lysis of red blood cells and consequent anemia. ©2013 Ferrata Storti Found.


Mesirca P.,Institute Of Genomique Fonctionnelle | Mesirca P.,Universites Of Montpellier 1 And 2 | Mesirca P.,French Institute of Health and Medical Research | Torrente A.G.,Institute Of Genomique Fonctionnelle | And 5 more authors.
Pflugers Archiv European Journal of Physiology | Year: 2014

Cardiac automaticity is a fundamental physiological function in vertebrates. Heart rate is under the control of several neurotransmitters and hormones and is permanently adjusted by the autonomic nervous system to match the physiological demand of the organism. Several classes of ion channels and proteins involved in intracellular Ca2+ handling contribute to pacemaker activity. Voltage-dependent T-type Ca2+ channels are an integral part of the complex mechanism underlying pacemaking. T-type channels also contribute to impulse conduction in mice and humans. Strikingly, T-type channel isoforms are co-expressed in the cardiac conduction system with other ion channels that play a major role in pacemaking such as f- (HCN4) and L-type Cav1.3 channels. Pharmacologic inhibition of T-type channels reduces the spontaneous activity of isolated pacemaker myocytes of the sino-atrial node, the dominant heart rhythmogenic centre. Target inactivation of T-type Ca v3.1 channels abolishes ICa,T in both sino-atrial and atrioventricular myocytes and reduces the daily heart rate of freely moving mice. Cav3.1 channels contribute also to automaticity of the atrioventricular node and to ventricular escape rhythms, thereby stressing the importance of these channels in automaticity of the whole cardiac conduction system. Accordingly, loss-of-function of Cav3.1 channels contributes to severe form of congenital bradycardia and atrioventricular block in paediatric patients. © 2014 Springer-Verlag.


Sah R.,Howard Hughes Medical Institute | Sah R.,Brigham and Women's Hospital | Mesirca P.,French National Center for Scientific Research | Mesirca P.,French Institute of Health and Medical Research | And 12 more authors.
Circulation | Year: 2013

Background- Transient receptor potential (TRP) channels are a superfamily of broadly expressed ion channels with diverse physiological roles. TRPC1, TRPC3, and TRPC6 are believed to contribute to cardiac hypertrophy in mouse models. Human mutations in TRPM4 have been linked to progressive familial heart block. TRPM7 is a divalent-permeant channel and kinase of unknown function, recently implicated in the pathogenesis of atrial fibrillation; however, its function in ventricular myocardium remains unexplored. Methods and Results-We generated multiple cardiac-targeted knockout mice to test the hypothesis that TRPM7 is required for normal ventricular function. Early cardiac Trpm7 deletion (before embryonic day 9; TnT/Isl1-Cre) results in congestive heart failure and death by embryonic day 11.5 as a result of hypoproliferation of the compact myocardium. Remarkably, Trpm7 deletion late in cardiogenesis (about embryonic day 13; αMHC-Cre) produces viable mice with normal adult ventricular size, function, and myocardial transcriptional profile. Trpm7 deletion at an intermediate time point results in 50% of mice developing cardiomyopathy associated with heart block, impaired repolarization, and ventricular arrhythmias. Microarray analysis reveals elevations in transcripts of hypertrophy/remodeling genes and reductions in genes important for suppressing hypertrophy (Hdac9) and for ventricular repolarization (Kcnd2) and conduction (Hcn4). These transcriptional changes are accompanied by action potential prolongation and reductions in transient outward current (Ito; Kcnd2). Similarly, the pacemaker current (If; Hcn4) is suppressed in atrioventricular nodal cells, accounting for the observed heart block. Conclusions-Trpm7 is dispensable in adult ventricular myocardium under basal conditions but is critical for myocardial proliferation during early cardiogenesis. Loss of Trpm7 at an intermediate developmental time point alters the myocardial transcriptional profile in adulthood, impairing ventricular function, conduction, and repolarization. © 2013 American Heart Association, Inc.

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