Universites Montpellier 1 and 2

Montpellier, France

Universites Montpellier 1 and 2

Montpellier, France
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Delatte H.,Universites Montpellier 1 and 2 | Toty C.,Universites Montpellier 1 and 2 | Boyer S.,Universites Montpellier 1 and 2 | Bouetard A.,Universites Montpellier 1 and 2 | And 2 more authors.
PLoS Neglected Tropical Diseases | Year: 2013

Arbovirus vector dynamics and spread are influenced by climatic, environmental and geographic factors. Major Chikungunya and Dengue fever outbreaks occurring the last 10 years have coincided with the expansion of the mosquito vector Aedes albopictus to nearly all the continents. We characterized the ecological (larval development sites, population dynamics, insemination and daily survival rates) and genetic (diversity, gene flow, population structure) features of two Aedes albopictus populations from distinct environments (rural and urban) on Réunion Island, in the South-West Indian Ocean. Microsatellite analysis suggests population sub-structuring Ae. albopictus populations. Two genetic clusters were identified that were significantly linked to natural versus urban habitats with a mixed population in both areas. Ae. albopictus individuals prefer urban areas for mating and immature development, where hosts and containers that serve as larval development sites are readily available and support high population densities, whereas natural environments appear to serve as reservoirs for the mosquito. © 2013 Delatte et al.


Comps-Agrar L.,French Institute of Health and Medical Research | Comps-Agrar L.,Universites Montpellier 1 and 2 | Comps-Agrar L.,Genentech | Kniazeff J.,French Institute of Health and Medical Research | And 8 more authors.
FASEB Journal | Year: 2012

The function of cell surface proteins likely involves the formation and dissociation of oligomeric complexes. However, the dynamics of this process are unknown. Here we examined this process for the GABAB receptors that assemble into oligomers of heterodimers through the association of their GABAB1subunit. We report a method to study oligomer dynamics based on a drug-controlled cell surface targeting of intracellularly retained receptors and a parallel measurement of two FRET signals in HEK293 cells. GABA B1 subunits at the cell surface (4.0±0.6 a.u.) are labeled with a pair of fluorophores (donor and red acceptor). New receptors are then targeted to the cell surface during 3h treatment with AP21967 such that the number of receptors is doubled (9.1±0.7 a.u.). After labeling these new receptors with a second acceptor (green), the red FRET remained unchanged (5189±36 vs. 4783±32 cps), supporting the stability of the preformed oligomers. However, new oligomers are detected by the green FRET signal indicating both receptor populations are in the same microdomains. As a control, we confirmed the strict stability of the GABAB heterodimer itself. Herein, using a novel method to monitor the dynamics of cell surface complexes, we provide evidence for the stability of GABAB oligomers. © FASEB.


Gutierrez-Mazariegos J.,CNRS Lyon Institute of Functional Genomics | Nadendla E.K.,Universites Montpellier 1 and 2 | Nadendla E.K.,University of Madras | Lima D.,The Interdisciplinary Center | And 11 more authors.
Endocrinology | Year: 2014

Nuclear receptors are transcription factors that regulate networks of target genes in response to small molecules. There is a strong bias in our knowledge of these receptors because they were mainly characterized in classical model organisms, mostly vertebrates. Therefore, the evolutionary origins of specific ligand-receptor couples still remain elusive. Here we present the identification and characterization of a retinoic acid receptor (RAR) from the mollusk Nucella lapillus (NIRAR). We show that this receptor specifically binds to DNA response elements organized in direct repeats as a heterodimer with retinoid X receptor. Surprisingly, we also find that NIRAR does not bind all-trans retinoic acid or any other retinoid we tested. Furthermore, NIRAR is unable to activate the transcription of reporter genes in response to stimulation by retinoids and to recruit coactivators in the presence of these compounds. Three-dimensional modeling of the ligand-binding domain of NIRAR reveals an overall structure that is similar to vertebrate RARs. However, in the ligand-binding pocket (LBP) of the mollusk receptor, the alteration of several residues interacting with the ligand has apparently led to an overall decrease in the strength of the interaction with the ligand. Accordingly, mutations of NIRAR at key positions within the LBP generate receptors that are responsive to retinoids. Altogether our data suggest that, in mollusks, RAR has lost its affinity for all-trans retinoic acid, highlighting the evolutionary plasticity of its LBP. When put in an evolutionary context, our results reveal new structural and functional features of nuclear receptors validated by millions of years of evolution that were impossible to reveal in model organisms. Copyright © 2014 by the Endocrine Society.


Delfosse V.,French Institute of Health and Medical Research | Delfosse V.,French National Center for Scientific Research | Delfosse V.,Universites Montpellier 1 and 2 | Grimaldi M.,Institute Of Recherche En Cancerologie Of Montpellier | And 13 more authors.
Vitamins and Hormones | Year: 2014

Bisphenol-A (BPA) is one of the highest-volume chemicals produced worldwide and the widespread exposure of individuals to BPA is suspected to affect a variety of physiological functions, including reproduction, development, and metabolism. Its estrogenic activity has been well documented in the last 15 years. In addition to estrogen receptors, BPA has been also shown to bind to and activate the estrogen-related receptor γ and pregnane X receptor and inhibit the androgen receptor. Halogenated BPAs were also shown to activate the peroxisome proliferator-activated receptor γ and inhibit thyroid hormone receptors. In this chapter, we review recent studies shedding light on the structural and molecular mechanisms by which BPA and its halogenated derivatives interfere with nuclear hormone receptor signaling. These data provide guidelines for the development of safer substitutes devoid of hormonal activity and may help environmental risk assessment. © 2014 Elsevier Inc.


PubMed | Universites Montpellier 1 and 2 and Universites Montpellier 1
Type: | Journal: Vitamins and hormones | Year: 2014

Bisphenol-A (BPA) is one of the highest-volume chemicals produced worldwide and the widespread exposure of individuals to BPA is suspected to affect a variety of physiological functions, including reproduction, development, and metabolism. Its estrogenic activity has been well documented in the last 15 years. In addition to estrogen receptors, BPA has been also shown to bind to and activate the estrogen-related receptor and pregnane X receptor and inhibit the androgen receptor. Halogenated BPAs were also shown to activate the peroxisome proliferator-activated receptor and inhibit thyroid hormone receptors. In this chapter, we review recent studies shedding light on the structural and molecular mechanisms by which BPA and its halogenated derivatives interfere with nuclear hormone receptor signaling. These data provide guidelines for the development of safer substitutes devoid of hormonal activity and may help environmental risk assessment.


Meffre J.,French National Center for Scientific Research | Meffre J.,French Institute of Health and Medical Research | Meffre J.,Universites Montpellier 1 and 2 | Chaumont-Dubel S.,French National Center for Scientific Research | And 25 more authors.
EMBO Molecular Medicine | Year: 2012

Cognitive deficits in schizophrenia severely compromise quality of life and are poorly controlled by current antipsychotics. While 5-HT6 receptor blockade holds special promise, molecular substrates underlying their control of cognition remain unclear. Using a proteomic strategy, we show that 5-HT6 receptors physically interact with several proteins of the mammalian target of rapamycin (mTOR) pathway, including mTOR. Further, 5-HT6 receptor activation increased mTOR signalling in rodent prefrontal cortex (PFC). Linking this signalling event to cognitive impairment, the mTOR inhibitor rapamycin prevented deficits in social cognition and novel object discrimination induced by 5-HT6 agonists. In two developmental models of schizophrenia, specifically neonatal phencyclidine treatment and post-weaning isolation rearing, the activity of mTOR was enhanced in the PFC, and rapamycin, like 5-HT6 antagonists, reversed these cognitive deficits. These observations suggest that recruitment of mTOR by prefrontal 5-HT6 receptors contributes to the perturbed cognition in schizophrenia, offering new vistas for its therapeutic control. © 2012 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.


Brami-Cherrier K.,French Institute of Health and Medical Research | Brami-Cherrier K.,University Pierre and Marie Curie | Brami-Cherrier K.,Institute du Fer a Moulin | Brami-Cherrier K.,University of California at Irvine | And 35 more authors.
EMBO Journal | Year: 2014

Focal adhesion kinase (FAK) controls adhesion-dependent cell motility, survival, and proliferation. FAK has kinase-dependent and kinase-independent functions, both of which play major roles in embryogenesis and tumor invasiveness. The precise mechanisms of FAK activation are not known. Using x-ray crystallography, small angle x-ray scattering, and biochemical and functional analyses, we show that the key step for activation of FAK's kinase-dependent functions-autophosphorylation of tyrosine-397-requires site-specific dimerization of FAK. The dimers form via the association of the N-terminal FERM domain of FAK and are stabilized by an interaction between FERM and the C-terminal FAT domain. FAT binds to a basic motif on FERM that regulates co-activation and nuclear localization. FAK dimerization requires local enrichment, which occurs specifically at focal adhesions. Paxillin plays a dual role, by recruiting FAK to focal adhesions and by reinforcing the FAT:FERM interaction. Our results provide a structural and mechanistic framework to explain how FAK combines multiple stimuli into a site-specific function. The dimer interfaces we describe are promising targets for blocking FAK activation. © 2014 The Authors.


Ayoub M.A.,Institute Of Genomique Fonctionnelle | Ayoub M.A.,Universites Montpellier 1 and 2 | Pin J.-P.,Institute Of Genomique Fonctionnelle | Pin J.-P.,Universites Montpellier 1 and 2
Frontiers in Endocrinology | Year: 2013

G protein-coupled receptors are well recognized as being able to activate several signaling pathways through the activation of different G proteins as well as other signaling proteins such as β-arrestins. Therefore, understanding how such multiple GPCR-mediated signaling can be integrated constitute an important aspect. Here, we applied bioluminescence resonance energy transfer (BRET) to shed more light on the G protein coupling profile of trypsin receptor, or protease-activated receptor 2 (PAR2), and its interaction with β-arrestin1. Using YFP and Rluc fusion constructs expressed in COS-7 cells, BRET data revealed a pre-assembly of PAR2 with both Gαi1 and Gαo and a rapid and transient activation of these G proteins upon receptor activation. In contrast, no pre-assembly of PAR2 with Gα12 could be detected and their physical association can be measured with a very slow and sustained kinetics similar to that of β-arrestin1 recruitment. These data demonstrate the coupling of PAR2 with Gαi1, Gαo, and Gα12 in COS-7 cells with differences in the kinetics of GPCR-G protein coupling, a parameter that very likely influences the cellular response. Moreover, this further illustrates that pre-assembly or agonist-induced G protein interaction depends on receptor-G protein pairs indicating another level of complexity and regulation of the signaling of GPCR-G protein complexes and its multiplicity. © 2013 Ayoub and Pin.


Corrales R.M.,Montpellier University | Leiba J.,Montpellier University | Cohen-Gonsaud M.,French Institute of Health and Medical Research | Cohen-Gonsaud M.,Universites Montpellier 1 and 2 | And 3 more authors.
Biochemical and Biophysical Research Communications | Year: 2013

S-Adenosylhomocysteine hydrolase (SahH) is known as an ubiquitous player in methylation-based process that maintains the intracellular S-adenosylhomocysteine (SAH) and S-adenosylmethionine (SAM) equilibrium. Given its crucial role in central metabolism in both eukaryotes and prokaryotes, it is assumed that SahH must be regulated, albeit little is known regarding molecular mechanisms governing its activity. We report here that SahH from Mycobacterium tuberculosis can be phosphorylated by mycobacterial Ser/Thr protein kinases and that phosphorylation negatively affects its enzymatic activity. Mass spectrometric analyses and site-directed mutagenesis identified Thr2 and Thr221 as the two phosphoacceptors. SahH_T2D, SahH_T221D and SahH_T2D/T221D, designed to mimic constitutive phosphorylation, exhibited markedly decreased activity compared to the wild-type enzyme. Both residues are fully conserved in other mycobacterial SahH orthologues, suggesting that SahH phosphorylation on Thr2 and Thr221 may represent a novel and presumably more general mechanism of regulation of the SAH/SAM balance in mycobacteria. © 2012 Elsevier Inc.


Cazade M.,Universites Montpellier 1 and 2 | Nuss C.E.,French Institute of Health and Medical Research | Bidaud I.,Universites Montpellier 1 and 2 | Renger J.J.,French Institute of Health and Medical Research | And 3 more authors.
Molecular Pharmacology | Year: 2014

ABSTRACT T-type calcium channels (T/Cav3-channels) are implicated in various physiologic and pathophysiologic processes such as epilepsy, sleep disorders, hypertension, and cancer. T-channels are the target of endogenous signaling lipids including the endocannabinoid anandamide, the v3-fatty acids, and the lipoamino-acids. However, the precise molecular mechanism by which these molecules inhibit T-current is unknown. In this study, we provided a detailed electrophysiologic and pharmacologic analysis indicating that the effects of the major N-acyl derivatives on the Cav3.3 current share many similarities with those of TTA-A2 [(R)-2-(4-cyclopropylphenyl)-N-(1-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)ethyl)acetamide], a synthetic Tchannel inhibitor. Using radioactive binding assays with the TTA-A2 derivative [3H]TTA-A1 [(R)-2-(4-(tert-butyl)phenyl)-N-(1- (5-methoxypyridin-2-yl)ethyl)acetamide], we demonstrated that polyunsaturated lipids, which inhibit the Cav3.3 current, as NAGly (N-arachidonoyl glycine), NASer (N-arachidonoyl-Lserine), anandamide, NADA (N-arachidonoyl dopamine), NATau (N-arachidonoyl taurine), and NA-5HT (N-arachidonoyl serotonin), all displaced [3H]TTA-A1 binding to membranes prepared from cells expressing Cav3.3, with Ki in a micromolar or submicromolar range. In contrast, lipids with a saturated alkyl chain, as N-arachidoyl glycine and N-arachidoyl ethanolamine, which did not inhibit the Cav3.3 current, had no effect on [3H]TTA-A1 binding. Accordingly, bio-active lipids occluded TTA-A2 effect on Cav3.3 current. In addition, TTAQ4 [(S)-4-(6-chloro-4-cyclopropyl-3- (2,2-difluoroethyl)-2- oxo-1,2,3,4-tetrahydroquinazolin-4-yl)benzonitrile], a positive allosteric modulator of [3H]TTA-A1 binding and TTA-A2 functional inhibition, acted in a synergistic manner to increase lipid-induced inhibition of the Cav3.3 current. Overall, our results demonstrate a common molecular mechanism for the synthetic T-channel inhibitors and the endogenous lipids, and indicate that TTA-A2 and TTA-Q4 could be important pharmacologic tools to dissect the involvement of T-current in the physiologic effects of endogenous lipids. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

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