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    Team: Functional Pharmacology and Pathophysiology of Membrane Receptors

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    Team leader:

     

    Membrane receptors are at the interface between the extracellular and intracellular environment and are thus crucial for cell communication. They are often organized in homo- or hetero-oligomeric complexes that respond to a wide variety of extracellular stimuli and that are the targets of most of the drugs prescribed for human diseases. Hormonal activation of these receptors leads to the recruitment of intracellular proteins and subsequent activation of intracellular signaling events. The adequate cellular response may vary depending on the cellular background and the pathophysiological state of the cell. Our objective is to first understand the dysfunction of membrane receptors in pathologies like obesity, diabetes and depression to then propose new original therapeutic strategies to cure these diseases.                                                                                              

     

     

     

     

    Objectives

     

    Mental disorders and metabolic diseases (obesity and type 2 diabetes) are major public health problems that involve defects in membrane receptor function. Targeting of these receptors or their associated protein complexes are promising strategies for the treatment of these diseases. We are currently investigating two membrane receptor families in this regard: the melatonin receptor family (MT1, MT2, GPR50 subtypes) and other receptors belonging to the G protein-coupled receptor super-family (http://www.gdr3545.com/) and leptin receptors belonging to the cytokine receptor family.

    Our international team uses pharmacological, endocrinological and proteomic approaches to understand the function of melatonin and leptin receptors and evaluate their therapeutic potential by developing innovative techniques such as BRET (Bioluminescence Resonance Energy Transfer) and time-resolved fluorescence resonance energy transfer (TR-FRET). These methods are complemented by several lentiviral-based gene transfer techniques and in vivo animal models.

    We are working on the following specific research axes:

    A)     The oligomerization of melatonin receptors and the impact of receptor oligomerization and receptor-associated complexes on MTR function

    B)     The identification and characterization of interacting partners of melatonin receptors

    C)    The relationship between the melatonin receptor family and mental disorders

    D)    The role of melatonin receptors in metabolic disorders

    E)     Interaction between leptin – OB-R

    F)     Modulation of OB-R function by the endospanin family

    G)    Leptin Transport into the brain

    H)    Gastro-intestinal hormones and the control of food intake

     

    Major Publications


    Bonnefond A*, Clement N*, Fawcett K, Yengo L, Vaillant E, Guillaume JL, Dechaume A, Payne F, Roussel R, Czernichow S, Hercberg S, Hadjadj S, Balkau B, Marre M, Lantieri O, Langenberg C, Bouatia-Naji N, MAGIC, Charpentier G, Vaxillaire M, Rocheleau G, Wareham NJ, Sladek R, McCarthy MI, Dina C, Barroso I, Jockers R* & Froguel P*.  Rare MTNR1B variants impairing melatonin MT2 receptor function contribute to type 2 diabetes. Nat Genetics, 44:297-301 (2012) (* equal contributions).
    Highlight in « Faits scientifiques 2012 » of Inserm.

    Baba K*, Benleulmi-Chaachoua A*, Journé AS, Kamal M, Guillaume JL, Dussaud S, Gbahou F, Yettou K, Liu C, Contreras-Alcantara S, Jockers R*, Tosini G*. Heteromeric MT1/MT2 Melatonin Receptors Modulate Photoreceptor Function. Science Signaling, Oct 8;6(296):ra89, (2013). (* equal contributions).
    Comment in: « Editor’s Choice » Science, 342 :535 (2013)

    Balland E, Dam J, Langlet F, Caron E, Steculorum S, Messina A, Rasika S, Falluel-Morel A, Anouar Y, Dehouck B, Trinquet E, Jockers R, Bouret SG, Prévot V. Hypothalamic tanycytes are an ERK-gated conduit for leptin into the brain. Cell Metabolism, 19 :293-301 (2014).

    Vauthier V, Swartz T, Chen P, Roujeau C, Pagnon M, Mallet J, Sarkis C,  Jockers R and Dam J. Endospanin 1 silencing in the hypothalamic arcuate nucleus contributes to sustained weight loss of high fat diet obese mice. Gene Therapy, 21:638-44 (2014).

    Ferré S, Casado V, Devis LA, Filizola M, Jockers R, Lohse MJ, Milligan G, Pin JP Guitart X. G Protein-Coupled Receptor Oligomerization Revisited: Functional and Pharmacological Perspectives. Pharma Rev, 66:413-434 (2014).

     

     Team news

     

    • Awards

    1. Obtained the label of Fondation pour la Recherche Médicale (FRM)-team in 2013

    2. Julie Dam, Laureate of the ANR Young Investigator program 2012

     

    •  Networks

    1. Member of the Labex «Who am I ?». Who am I? is a large, cooperative and multi-disciplinary research project focusing on the fundamental question of the origin of identity

    2. Member of the DHU (Département Hospitalo-Universitaire) AUTHORS «Maladies hormonales et auto-immunes» created in 2013

    3. Direction of the Groupement de Recherche GDR-3545  “RCPG-Physio-Med”.
    The GDR-3545 on “G Protein-coupled Receptors : from physiology to drugs (RCPG-Physio-Med)” was created in 2012 by the CNRS

    •  Multimedia, Popular Science, Foundations

    1. Pint of Science, festival of science for the public (May 19th, 2014):
    « Quand nos hormones s’affolent: mieux comprendre les dérégulations du métabolisme, l’obésité et le diabète »
    « Corriger la résistance à la leptine pour combattre l'obésité », J. Dam
    « La mélatonine et le diabète », R Jockers

    2. Interview for « HORIZON » Magazine  of the European Commission on « Obesity genes reveal why we eat too much « (J. Dam, R Jockers, EurOCHIP consortium Partner) (August 6th, 2014).

    3. Participation in the visit of the« Conseil de surveillance » of the Fondation pour la Recherche Médicale (September 17th, 2014).

    4. Participation in the “Nutrition Métabolisme » event organized on the occasion of the 50th anniversary of INSERM and "Les Chercheurs accueillent les Malades" (October 3rd, 2014).

     

     

    Financial supports