Institute Of Genomique Fonctionnelle

Montpellier, France

Institute Of Genomique Fonctionnelle

Montpellier, France
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Gangarossa G.,French National Center for Scientific Research | Gangarossa G.,French Institute of Health and Medical Research | Gangarossa G.,Universites Of Montpellier 1 And 2 | Laffray S.,French National Center for Scientific Research | And 10 more authors.
Frontiers in Behavioral Neuroscience | Year: 2014

The fine-tuning of neuronal excitability relies on a tight control of Ca2+ homeostasis. The low voltage-activated (LVA) T-type calcium channels (Cav3.1, Cav3.2 and Cav3.3 isoforms) play a critical role in regulating these processes. Despite their wide expression throughout the central nervous system, the implication of T-type Cav3.2 isoform in brain functions is still poorly characterized. Here, we investigate the effect of genetic ablation of this isoform in affective disorders, including anxiety, cognitive functions as well as sensitivity to drugs of abuse. Using a wide range of behavioral assays we show that genetic ablation of the cacna1h gene results in an anxiety-like phenotype, whereas novelty-induced locomotor activity is unaffected. Deletion of the T-type channel Cav3.2 also triggers impairment of hippocampus-dependent recognition memories. Acute and sensitized hyperlocomotion induced by d-amphetamine and cocaine are dramatically reduced in T-type Cav3.2 deficient mice. In addition, the administration of the T-type blocker TTA-A2 prevented the expression of locomotor sensitization observed in wildtype mice. In conclusion, our data reveal that physiological activity of this specific Ca2+ channel is required for affective and cognitive behaviors. Moreover, our work highlights the interest of T-type channel blockers as therapeutic strategies to reverse drug-associated alterations. © 2014 Gangarossa, Laffray, Bourinet and Valjent.


Jitsuki S.,Yokohama City University | Takemoto K.,Yokohama City University | Takemoto K.,Japan Science and Technology Agency | Kawasaki T.,Yokohama City University | And 11 more authors.
Neuron | Year: 2011

Loss of one type of sensory input can cause improved functionality of other sensory systems. Whereas this form of plasticity, cross-modal plasticity, is well established, the molecular and cellular mechanisms underlying it are still unclear. Here, we show that visual deprivation (VD) increases extracellular serotonin in the juvenile rat barrel cortex. This increase in serotonin levels facilitates synaptic strengthening at layer 4 to layer 2/3 synapses within the barrel cortex. Upon VD, whisker experience leads to trafficking of the AMPA-type glutamate receptors (AMPARs) into these synapses through the activation of ERK and increased phosphorylation of AMPAR subunit GluR1 at the juvenile age when natural whisker experience no longer induces synaptic GluR1 delivery. VD thereby leads to sharpening of the functional whisker-barrel map at layer 2/3. Thus, sensory deprivation of one modality leads to serotonin release in remaining modalities, facilitates GluR1-dependent synaptic strengthening, and refines cortical organization. © 2011 Elsevier Inc.


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.


Rondard P.,Institute Of Genomique Fonctionnelle | Rondard P.,French Institute of Health and Medical Research | Goudet C.,Institute Of Genomique Fonctionnelle | Goudet C.,French Institute of Health and Medical Research | And 6 more authors.
Neuropharmacology | Year: 2011

In the human genome, 22 genes are coding for the class C G protein-coupled receptors that are receptors for the two main neurotransmitters glutamate and γ-aminobutyric acid, for Ca2+ and for sweet and amino acid taste compounds. In addition to the GPCR heptahelical transmembrane domain responsible for G-protein activation, class C receptors possess a large extracellular domain that is responsible for ligand recognition. Recent studies had revealed that class C receptors are homo- or heterodimers with unique mechanism of activation. In the present review, we present an up-to-date view of the structures and activation mechanism of these receptors in particular the metabotropic glutamate and GABAB receptors. We show how the complexity of functioning of these transmembrane proteins can be used for the development of therapeutics to modulate their activity. We emphasize on the new approaches and drugs that could potentially become important in the future pharmacology of these receptors. © 2010.


Gangarossa G.,Institute Of Genomique Fonctionnelle | Gangarossa G.,French Institute of Health and Medical Research | Gangarossa G.,French National Center for Scientific Research | Gangarossa G.,Montpellier University | And 4 more authors.
Neuropharmacology | Year: 2012

Acute systemic administration of the dopamine D1/D5 receptors (D1Rs) agonist, SKF81297, activates the extracellular signal-regulated protein kinases (ERK) pathway selectively in the granule cells of the dentate gyrus. In this study, we examined the mechanisms involved in this regulation and investigated the molecular components that could promote ERK-dependent transcription and translation. SKF81297 induced phosphorylation of ERK and histone H3 required intact glutamatergic transmission. Blockade of glutamate release achieved by the mGluR2/3 agonist, LY354740 or the selective adenosine A1R agonist, CCPA as well as neurotoxic lesions of lateral entorhinal cortex reduced the ability of SKF81297 to induce ERK activation in the dentate gyrus. This activation required the combined stimulation of NR2B-containing NMDARs, mGluR1 and mGluR5. SKF81297 evoked phosphorylation of the ribosomal protein S6 (rpS6) selectively at the Ser235/236 site while the Ser240/244 site remains unchanged. The SKF81297 induced increased phosphorylation of rpS6 was dependent on PKC and ERK/p90RSK activation. Surprisingly, administration of D1Rs agonist suppressed mTORC1/p70S6K pathway suggesting an mTOR-independent regulation of rpS6 phosphorylation. Taken together, our results show that intact glutamatergic transmission plays a major role in the regulation of ERK-dependent phosphorylation of histone H3 and rpS6 observed in the mouse dentate gyrus after systemic administration of SKF81297. Highlights: SKF81297 induced ERK, histone H3 and ribosomal S6 phosphorylation in the dentate gyrus requires group I mGluRs stimulation. PKC is involved in SKF81297 induced ERK cascade activation. Ribosomal S6 phosphorylation is independent of mTORC1 pathway. © 2012 Elsevier Ltd. All rights reserved.


Boisguerin P.,Montpellier University | Giorgi J.-M.,Montpellier University | Barrere-Lemaire S.,Institute Of Genomique Fonctionnelle
Current Pharmaceutical Design | Year: 2013

Acute myocardial infarction (AMI) is a frequent and disabling disease, which is the first cause of cardiovascular mortality worldwide. Infarct size is a major determinant of myocardial functional recovery and mortality after AMI. Limitation of infarct size thus appears as an appropriate strategy to prevent post-ischemic heart failure and improve survival. Reperfusion is the only treatment recommended to reduce infarct size but despite obvious benefits, it may also have deleterious effects called ischemia-reperfusion (IR) injury including myocyte cell death. Proteins involved in the apoptosis cascade generally interact over large surfaces lacking well-defined pockets. Therefore, inhibitory peptides are optimal biomolecules to target these large protein surfaces, they are often more selective to their target than conventional small organic molecules, and they can be tailored for optimal affinity or desired metabolic property. Since peptides do not cross freely biological membranes, they are generally administered in association with cell penetrating peptides (CPPs) and with homing peptides (HPs) for selective organs or tissues targeting. As a first approach in vivo, we made use of the already known BH4 peptidic inhibitor of the mitochondrial apoptotic pathway, which showed cardioprotective properties in a murine model of AMI after a single bolus of intravenous administration. More importantly, similar peptidic strategies and tools are likely to be adaptable to many other situations in which cells have to be protected from apoptosis such as stroke or organ transplantation. © 2013 Bentham Science Publishers.


Mouillac B.,Institute Of Genomique Fonctionnelle | Baneres J.L.,Institute Of Genomique Fonctionnelle
Methods in molecular biology (Clifton, N.J.) | Year: 2010

Integral membrane proteins, in particular receptors, regulate numerous physiological functions. The primary difficulty presented by their study in vitro is to obtain them in sufficient amounts in a functional state. Escherichia coli is a host of choice for producing recombinant proteins for structural studies. However, insertion of G-protein coupled receptors into its plasma membrane usually results in bacterial death. An alternative approach consists of targeting recombinant receptors to inclusion bodies, where they accumulate without affecting bacterial growth, and then fold them in vitro . We describe here a general approach that consists of accumulating the receptor in bacterial inclusion bodies, then purifying it under denaturing conditions. A simple assay is then described to screen for refolding conditions of the protein.


Combes M.-C.,Montpellier University | Dereeper A.,Montpellier University | Severac D.,Institute Of Genomique Fonctionnelle | Bertrand B.,Montpellier University | Lashermes P.,Montpellier University
New Phytologist | Year: 2013

Polyploidy has occurred throughout the evolutionary history of plants and led to diversification and plant ecological adaptation. Functional plasticity of duplicate genes is believed to play a major role in the environmental adaptation of polyploids. In this context, we characterized genome-wide homoeologous gene expression in Coffea arabica, a recent allopolyploid combining two subgenomes that derive from two closely related diploid species, and investigated its variation in response to changing environment. The transcriptome of leaves of C. arabica cultivated at different growing temperatures suitable for one or the other parental species was examined using RNA-sequencing. The relative contribution of homoeologs to gene expression was estimated for 9959 and 10 628 genes in warm and cold conditions, respectively. Whatever the growing conditions, 65% of the genes showed equivalent levels of homoeologous gene expression. In 92% of the genes, relative homoeologous gene expression varied < 10% between growing temperatures. The subgenome contributions to the transcriptome appeared to be only marginally altered by the different conditions (involving intertwined regulations of homeologs) suggesting that C. arabica's ability to tolerate a broader range of growing temperatures than its diploid parents does not result from differential use of homoeologs. © 2013 New Phytologist Trust.


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.


Bockaert J.,Institute Of Genomique Fonctionnelle
Medecine/Sciences | Year: 2012

The 2012 Nobel Prize for chemistry has been won by Robert J. Lefkowitz and Brian Kobilka for their work on G protein-coupled receptors (GPCRs). Those receptors (3% of human genome) evolutionary are derived from one 1 or 2 ancestors and are able to recognize external message as different as light, odorants, gustative molecules and intercellular messages such as hormones and neurotransmitters. They are targets of 30-40% of therapeutic drugs. Robert J. Lefkowitz has been one of the leaders of the field from more than 40 years and has built several key concepts of the domain. Brian Kobilka was successful, in 2007, in producing a crystal structure of the ?2-adrenergic receptor. This paved the way for the production of a series of almost 50 GPCR crystal structures both in inactive and active forms.

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