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Team: Functional Pharmacology and Pathophysiology of Membrane Receptors

Team leader:

	Ralf Jockers DR1 INSERM

The team, directed by Ralf Jockers, including a group led by Julie Dam, is interested in understanding the function of membrane receptors in metabolic diseases. Membrane receptors are at the interface between the extracellular and intracellular environment and are thus crucial for cell communication. They respond to a wide variety of extracellular stimuli and are the targets of most of the drugs prescribed for human diseases. Hormonal activation of these receptors leads to the activation of intracellular signaling events. However, the adequate response may vary depending on the genetic background and the disease state of individuals.

Our objective is to understand the dysfunction of membrane receptors in metabolic diseases like obesity and diabetes among others. Both diseases constitute major public health problems with 1.5 billion people being over-weight, more than 500 million people being obese and more than 350 million people having diabetes worldwide. There is therefore an urgent need for innovative therapeutic approaches.

Objectives

We are interested in the investigation of the involvement of membrane receptors in metabolic diseases such as obesity and diabetes and its link to Alzheimer disease . We are particularly focusing our research on two membrane receptor families, the G protein-coupled receptor (GPCR) family and the cytokine receptor family to which the leptin receptor belongs. Among the various GPCRs studied the group has a major expertise on the melatonin receptor sub-family.
We are employing cutting-edge biochemical, pharmacological, endocrinological and proteomic approaches to understand the function of these receptors and evaluate their therapeutic potential by developing innovative techniques such as Bioluminescence Resonance Energy Transfer (BRET), Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) and enzyme complementation. These methods are complemented with the investigation of knock-out and knock-in mouse models.
We are an international team of scientists coming from over ten different countries. Regular visiting PhD students, post-docs and senior scientists contribute to a highly cross-stimulating research environment. Established relationships with industrial partners allow the fast translation of our research results.

5 Major Publications

Karamitri A and Jockers R. Melatonin in type 2 diabetes and obesity. Nat Rev Endocrinol. 2018 Dec 7. doi: 10.1038/s41574-018-0130-1
Karamitri A, Plouffe B, Bonnefond A, Chen M, Gallion J, Guillaume JL, Hegron A, Boissel M, Canouil M, Langenberg C, Wareham NJ, Le Gouill C, Lukashova V, Lichtarge O, Froguel P, Bouvier M and Jockers R. Melatonin MT2 Receptor Variants Associated with Type 2 Diabetes Affect Specific Subsets of the Receptor Signaling Modalities. Science Signaling, 2018, 11(545). pii: eaan6622.
See Institute news: A study directed by Ralf Jockers and INSERM news
Wojciech S*, Ahmad R *, Belaid-Choucair Z, Journé AS, Gallet S, Dam J, Daulat A, Ndiaye-Lobry D, Lahuna O, Karamitri A, Guillaume JL, Do Cruzeiro M, Guillonneau F, Saade A, Clément N, Courivaud T, Kaabi N, Tadagaki K, Delagrange P, Prévot V, Hermine O, Prunier C and Jockers R. The orphan GPR50 receptor promotes constitutive TGFβ receptor signaling and protects against cancer development. Nature Comm, 9:1216 (2018)
See INSERM news and CNRS news
Vauthier V*, Roujeau C*, Chen P, Sarkis S, Migrenne S, Hoisi T, Ozawa K, Rouille Y, Foretz M, Mallet J, Launay JM, Magnan C, Jockers R, Dam J. Endospanin 1 affects oppositely body weight regulation and glucose homeostasis by differentially regulating central leptin signaling. Mol Metabolism, 6(1):159-172 (2016).
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)
See press release : Highlight in « Faits scientifiques 2012 » of Inserm.
(* equal contributions)

Team news

Highlights

- The team is mobilized against COVID-19:
* Participation to Exscalate4CoV (Accelerating the search for drugs against COVID-19)
* Collaboration with the team of Pr Subhabrata Sen from Shiv-Nadar University (India)
* MELATOVID project

- Link between obesity/type 2 diabetes and Alzheimer disease: amyloïde-bêta peptide is a negative allosteric modulator of the leptin receptor (2020)
See News from the Institut Cochin, News from Inserm, Fondation Chatrier and « Alzheimer La Radio »

- GPR50 and direct regulation of gene expression (2020)
Our study describes an alternative signaling mode of GPCRs at the nucleus level, by the GPR50 receptor, which is based on the nuclear translocation of its intracellular domain and the direct regulation of gene expression
Cell Mol Life Sci (2020)

- Melatonin and type 2 diabetes - the link becomes clearer
Linking melatonin receptor variants to signal differences leads to potential new therapeutics of type 2 diabetes
See News from Inserm, News from the Institut Cochin

- A new duo for the protection of breast cancer: the heterodimer complex GRP50 – TβRI
Free access article in Nat Comm (2018) 9:1216

- Endospanin 1, a regulator of the leptin receptor dissociates the development of obesity and type2 diabetes
See in Neuroendocrinology (2019) and Medecine/Sciences (2018)

- Development of novel technological assays and biosensors to assess the pharmacology of disease-associated receptors
ACS Sensors (2020), Free access article in Br J Pharmacol (2019) and Biochem Pharmacol (2018)

- Synthesis and characterization of first cell-impermeant and biased melatonin receptor ligands demonstrating functional expression of MT₁ receptors in mitochondria
See on vimeo.com and YouTube, Free access article in Br J Pharmacol 2017 174:2409-21 and Proc Natl Acad Sci U S A (2017) E7997-E8006

- Latest reference review on melatonin receptors: Update on melatonin receptors: IUPHAR Review 2016
Free access article in Br J Pharmacol (2016) 173:2702-25

- Lab retreat 2019

some photos, other photos......and more

Awards

2020 - Support from the Fondation de France (2020) in cardiometabolism and neurodegenerative diseases (Julie Dam)

2019 - The team obtained for the 3^rd time the label of Fondation pour la Recherche Médicale (FRM)

2017 - Marie Sklodowska-Curie Actions Seal of Excellence awarded to Atsuro Oishi and our team

2016 - Best poster price for research engineers (INTERCHIM price) awarded to Marine Luka at the GDR-3545 meeting in Tours

2015 - Price of the Fondation Philippe Chatrier awarded to Erika Cecon

2013 - The team obtained the label of Fondation pour la Recherche Médicale (FRM)- 2013
Julie Dam, Laureate of the ANR Young Investigator program 2012

Networks

ERNEST (European Research Network on Signaling)
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
Member of the Départements Hospitalo Universitaires (DHU) AUTHORS « Autoimmune and hormonal diseases »
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
Pharmacological targets (IUPHAR)
GPCR database (GPCRdb)
Protein data bank (PDB)
Melatonin receptors

Charity event participation

2018 - Running to support type1 diabetes

2016-2017 - Several golf competition organized
by Chatrier Fondation to support Alzheimer research

2016 - ODYSSÉA PARIS 2016 to support cancer research

Multimedia, Popular Science, Foundations

Link between metabolic disorders and Alzheimer disease « Alzheimer La Radio »
Organized by the "Société de Biologie": Signaling in intracellular compartments: a new paradigm (Curie Institute, 2018)
Traffic and signaling of the leptin receptor
Mitochondrial signaling of G protein coupled receptors
Video production of article abstract of the team (Gbahou, Cecon et al. Br J Pharmacol, 2017) - See on vimeo.com and YouTube
Photo shooting for France Alzheimer, May 2017
Interview Journal Science & Avenir, "A chinese plant against obesity", July, 2015
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).
Participation in the visit of the "Conseil de surveillance" of the Fondation pour la Recherche Médicale (September, 2014).
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, 2014).
Pint of Science (J. Dam, R Jockers,(May 2014)

Visiting scientists

Visiting PhD students:
2013 - Erika CECON (Brazil)
2015 - Sharon OWINO (USA)
2017 - Francesca PIAGGIO (Italy)
2018 - Ana DUARTE NOSEDA (Brazil)

Visiting post-docs:
2015 - Min PARK (Singapore)
2016 - Atsuro OISHI (Japan)

Visiting professors:
2016 - Gianluca TOSINI (USA) “Who Am I” Labex visiting professor
2018 - Toru HOSOI (Japan)
2019 - Toru HOSOI (Japan), Japan Society for the Promotion of Science (KAKENHI)