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Jean-Philippe Pin

Directeur de Recherche de classe exceptionnelle au CNRS
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  • 1087315
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Jean-Philippe Pin got his PhD in Molecular Biology in 1987 at the University of Montpellier (France), working on excitatory amino acids receptors, at a time when glutamate was not yet fully accepted as a neurotransmitter. His studies led him to participate in 1985 in the discovery of G protein-coupled glutamate receptors, known as the metabotropic glutamate receptors. Since then, he has been concentrated on studying these fascinating dimeric and multidomain receptors. Using innovative tricks and assays co-developed with the CisBio company, he revealed any details of their original activation mechanism from the agonist-induced closure of the extracellular binding domain, to the relative movement of the two subunits, leading to a specific dimer interface of the active state allowing one subunit only to activate G proteins. These studies were extended to most class C GPCRs including the Calcium sensing and the GABAB receptor. Thanks to his collaborative laboratory established in China, he participated in the determination of the cryo-EM structure of some of these receptors, and revealed the original mode of G protein activation, different from that of all other GPCRs. Recently, he demonstrated the existence of heterodimeric mGluRs in the brain, adding sixteen possible new mGluRs in the brain. His studies were dedicated to the development of innovative molecules with the aim to decipher the therapeutic potential of these targets. Along these lines, he was among the first to report inverse agonists, as well as both negative and positive allosteric modulators for mGluRs. More recently, he has been developing original tools, including photoswitchable allosteric ligands that allowed him to demonstrate the role of central mGlu4 in the pain response, or allosteric nanobodies able to ameliorate the cognitive deficit in a mouse model of schizophrenia. In conclusion, over the recent years he developed innovative approaches to study cell surface receptors, including biosensors, photoswitchable ligands and nanobodies as pharmacological tools and potential therapeutic agents. His studies led to new concepts in the GPCR field, such as: the activation of cell surface receptors by intracellular proteins; the regulation of GPCRs by both negative and positive allosteric modulators, the asymmetric functioning of GPCR dimers.
Jean-Philippe Pin a obtenu son doctorat en biologie moléculaire en 1987 à l'université de Montpellier (France), en travaillant sur les récepteurs des acides aminés excitateurs, à une époque où le glutamate n'était pas encore pleinement accepté comme neurotransmetteur. Ses études l'ont amené à participer en 1985 à la découverte des récepteurs du glutamate couplés à la protéine G, connus sous le nom de récepteurs métabotropiques du glutamate. Depuis lors, il s'est concentré sur l'étude de ces fascinants récepteurs dimériques et multidomaines. À l'aide d'astuces et de tests innovants développés en collaboration avec la société CisBio, il a révélé tous les détails de leur mécanisme d'activation original, depuis la fermeture du domaine de liaison extracellulaire induite par l'agoniste jusqu'au mouvement relatif des deux sous-unités, conduisant à une interface dimérique spécifique de l'état actif permettant à une seule sous-unité d'activer les protéines G. Ces études ont été étendues à la plupart des récepteurs de la classe C. Ces études ont été étendues à la plupart des GPCRs de classe C, y compris la détection du calcium et le récepteur GABAB. Grâce à son laboratoire collaboratif établi en Chine, il a participé à la détermination de la structure cryo-EM de certains de ces récepteurs, et a révélé le mode original d'activation de la protéine G, différent de celui de tous les autres RCPG. Récemment, il a démontré l'existence de mGluR hétérodimériques dans le cerveau, ajoutant seize nouveaux mGluR possibles dans le cerveau. Ses études ont été consacrées au développement de molécules innovantes dans le but de décrypter le potentiel thérapeutique de ces cibles. Dans cette optique, il a été l'un des premiers à signaler l'existence d'agonistes inverses, ainsi que de modulateurs allostériques négatifs et positifs pour les mGluRs. Plus récemment, il a développé des outils originaux, notamment des ligands allostériques photoswitchables qui lui ont permis de démontrer le rôle du mGlu4 central dans la réponse à la douleur, ou des nanocorps allostériques capables d'améliorer le déficit cognitif dans un modèle murin de schizophrénie. En conclusion, au cours des dernières années, il a développé des approches innovantes pour étudier les récepteurs de la surface cellulaire, y compris les biocapteurs, les ligands photosensibles et les nanocorps en tant qu'outils pharmacologiques et agents thérapeutiques potentiels. Ses études ont débouché sur de nouveaux concepts dans le domaine des RCPG, tels que l'activation des récepteurs de surface cellulaire par des protéines intracellulaires, la régulation des RCPG par des modulateurs allostériques négatifs et positifs, le fonctionnement asymétrique des dimères de RCPG.

Research domains

Neurobiology Biotechnology Biochemistry [q-bio.BM] Molecular biology Biophysics Pharmacology

Publications

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Different EGF ‐induced receptor dimer conformations for signaling and internalization

Jordi Haubrich , Jurriaan Zwier , Fabienne Charrier-Savournin , Laurent Prézeau , Jean‐philippe Pin
FASEB Journal, 2024, 38 (1), pp.e23356. ⟨10.1096/fj.202301209R⟩
Journal articles hal-04472295v1

Synthesis and pharmacological characterization of conformationally restricted 2-amino-Adipic acid analogs and carboxycyclopropyl glycines as selective metabotropic glutamate 2 receptor agonists

Markus Staudt , Na Liu , Fanny Malhaire , Yasaman Doroudian , Laurent Prézeau
European Journal of Medicinal Chemistry, 2024, 266, pp.116157. ⟨10.1016/j.ejmech.2024.116157⟩
Journal articles hal-04415292v1
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Specific pharmacological and Gi/o protein responses of some native GPCRs in neurons

Chanjuan Xu , Yiwei Zhou , Yuxuan Liu , Li Lin , Peng Liu
Nature Communications, 2024, 15 (1), pp.1990. ⟨10.1038/s41467-024-46177-z⟩
Journal articles hal-04492538v1
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TrkB receptor interacts with mGlu 2 receptor and mediates antipsychotic-like effects of mGlu 2 receptor activation in the mouse

Clémentine Eva Philibert , Candice Disdier , Pierre-André Lafon , Alexandre Bouyssou , Mathieu Oosterlaken
Science Advances , 2024, 10 (4), pp.eadg1679. ⟨10.1126/sciadv.adg1679⟩
Journal articles hal-04429823v1

Design, Synthesis, Pharmacology, and In Silico Studies of (1 S ,2 S ,3 S )-2-(( S )-Amino(carboxy)methyl)-3-(carboxymethyl)cyclopropane-1-carboxylic Acid (LBG30300): A Picomolar Potency Subtype-Selective mGlu 2 Receptor Agonist

Na Liu , Floriane Eshak , Fanny Malhaire , Isabelle Brabet , Laurent Prézeau
Journal of Medicinal Chemistry, 2024, 67 (2), pp.1314-1326. ⟨10.1021/acs.jmedchem.3c01811⟩
Journal articles hal-04385775v1
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Concerted conformational changes control metabotropic glutamate receptor activity

Nathalie Lecat-Guillet , Robert Quast , Hongkang Liu , Emmanuel Bourrier , Thor Møller
Science Advances , 2023, 9 (22), pp.eadf1378. ⟨10.1126/sciadv.adf1378⟩
Journal articles hal-04121751v1
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Targeting the Brain with Single-Domain Antibodies: Greater Potential Than Stated So Far?

Mireille Elodie Tsitokana , Pierre-André Lafon , Laurent Prézeau , Jean-Philippe Pin , Philippe Rondard
International Journal of Molecular Sciences, 2023, 24 (3), pp.2632. ⟨10.3390/ijms24032632⟩
Journal articles hal-03991195v1

( S )-2-Mercaptohistidine: A First Selective Orthosteric GluK3 Antagonist

Christian Poulie , Younes Larsen , Cindie Leteneur , Gaël Barthet , Walden Bjørn-Yoshimoto
ACS Chemical Neuroscience, 2022, 13 (10), pp.1580-1587. ⟨10.1021/acschemneuro.2c00162⟩
Journal articles hal-03659473v1
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Chronic sodium bromide treatment relieves autistic-like behavioral deficits in three mouse models of autism

Cécile Derieux , Audrey Léauté , Agathe Brugoux , Déborah Jaccaz , Claire Terrier
Neuropsychopharmacology, 2022, 47 (9), pp.1680-1692. ⟨10.1038/s41386-022-01317-1⟩
Journal articles hal-03647444v1
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Nanobody-based sensors reveal a high proportion of mGlu heterodimers in the brain

Jiyong Meng , Chanjuan Xu , Pierre-André Lafon , Salomé Roux , Michaël Mathieu
Nature Chemical Biology, 2022, 18, pp.894-903. ⟨10.1038/s41589-022-01050-2⟩
Journal articles hal-03699580v1
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Structural basis of the activation of metabotropic glutamate receptor 3

Wei Fang , Fan Yang , Chanjuan Xu , Shenglong Ling , Li Lin
Cell Research, 2022, 32 (7), pp.695-698. ⟨10.1038/s41422-022-00623-z⟩
Journal articles hal-03603715v1
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SGIP1 modulates kinetics and interactions of the cannabinoid receptor 1 and G protein‐coupled receptor kinase 3 signalosome

Matej Gazdarica , Judith Noda , Oleh Durydivka , Vendula Novosadova , Ken Mackie
Journal of Neurochemistry, 2022, 160 (6), pp.625-642. ⟨10.1111/jnc.15569⟩
Journal articles hal-03761588v1
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Biased signaling due to oligomerization of the G protein-coupled platelet-activating factor receptor

Junke Liu , Hengmin Tang , Chanjuan Xu , Shengnan Zhou , Xunying Zhu
Nature Communications, 2022, 13 (1), pp.6365. ⟨10.1038/s41467-022-34056-4⟩
Journal articles hal-03837051v1
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GABAB1e promotes the malignancy of human cancer cells by targeting the tyrosine phosphatase PTPN12

Bo Wei , Yini Zhu , Peng Yang , Yong Han , Suyun Wang
iScience, 2021, 24 (11), pp.103311. ⟨10.1016/j.isci.2021.103311⟩
Journal articles hal-03432362v1
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Structures of human mGlu2 and mGlu7 homo- and heterodimers

Juan Du , Dejian Wang , Hongcheng Fan , Chanjuan Xu , Linhua Tai
Nature, 2021, 594 (7864), pp.589-593. ⟨10.1038/s41586-021-03641-w⟩
Journal articles hal-03269110v1
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Agonists and allosteric modulators promote signaling from different metabotropic glutamate receptor 5 conformations

Chady Nasrallah , Giuseppe Cannone , Julie Briot , Karine Rottier , Alice Berizzi
Cell Reports, 2021, 36 (9), pp.109648. ⟨10.1016/j.celrep.2021.109648⟩
Journal articles hal-03340751v1
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Allosteric ligands control the activation of a class C GPCR heterodimer by acting at the transmembrane interface

Lei Liu , Zhiran Fan , Xavier Rovira , Li Xue , Salomé Roux
eLife, 2021, 10, pp.e70188. ⟨10.7554/eLife.70188⟩
Journal articles hal-03738955v1
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Structural basis of GABAB receptor–Gi protein coupling

Cangsong Shen , Chunyou Mao , Chanjuan Xu , Nan Jin , Huibing Zhang
Journal articles hal-03218736v1

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein‐coupled receptors

Stephen Alexander , Arthur Christopoulos , Anthony Davenport , Eamonn Kelly , Alistair Mathie
British Journal of Pharmacology, 2021, 178 (S1), pp.e0243333. ⟨10.1111/bph.15538⟩
Journal articles hal-03875300v1
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Allosteric modulators enhance agonist efficacy by increasing the residence time of a GPCR in the active state

Anne-Marinette Cao , Robert B Quast , Fataneh Fatemi , Philippe Rondard , Jean-Philippe Pin
Nature Communications, 2021, 12 (1), pp.5426. ⟨10.1038/s41467-021-25620-5⟩
Journal articles hal-03352901v2
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The GABA B receptor mediates neuroprotection by coupling to G 13

Yunyun Wang , Siyu Gai , Wenhua Zhang , Xuetao Huang , Shumin Ma
Science Signaling, 2021, 14 (705), pp.eaaz4112. ⟨10.1126/scisignal.aaz4112⟩
Journal articles hal-03394399v1
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A nanobody activating metabotropic glutamate receptor 4 discriminates between homo- and heterodimers

Jordi Haubrich , Joan Font , Robert Quast , Anne Goupil-Lamy , Pauline Scholler
Proceedings of the National Academy of Sciences of the United States of America, 2021, 118 (33), pp.e2105848118. ⟨10.1073/pnas.2105848118⟩
Journal articles hal-03322348v1
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G protein‐coupled receptors can control the Hippo/YAP pathway through Gq signaling

Diana Zindel , Patrick Mensat , Claire Vol , Zeinab Homayed , Fabienne Charrier‐savournin
FASEB Journal, 2021, 35 (7), pp.e21668. ⟨10.1096/fj.202002159R⟩
Journal articles hal-03263933v1
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Structural basis for distinct quality control mechanisms of Drosophila and mammalian GABAB receptor

Shenglan Zhang , Li Xue , Xuehui Liu , Xuejun Cai Zhang , Rui Zhou
FASEB Journal, 2020, 34 (12), pp.16348-16363. ⟨10.1096/fj.202001355RR⟩
Journal articles hal-03065658v1
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Structural basis of metabotropic GABA receptor activation

Hamidreza Shaye , Andrii Ishchenko , Jordy Homing Lam , Gye Won Han , Li Xue
Nature, 2020, 584 (7820), pp.298-303. ⟨10.1038/s41586-020-2408-4⟩
Journal articles hal-03065675v1
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Illuminating the allosteric modulation of the calcium-sensing receptor

Hongkang Liu , Ping Yi , Wenjing Zhao , Yuling Wu , Francine Acher
Proceedings of the National Academy of Sciences of the United States of America, 2020, 117 (35), pp.21711-21722. ⟨10.1073/pnas.1922231117⟩
Journal articles hal-02933760v1
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D1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson’s disease

Irene Sebastianutto , Elise Goyet , Laura Andreoli , Joan Font-Ingles , David Moreno-Delgado
Journal of Clinical Investigation, 2020, 130 (3), pp.1168 - 1184. ⟨10.1172/JCI126361⟩
Journal articles hal-02476033v1
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GPCR interaction as a possible way for allosteric control between receptors

Jean-Philippe Pin , Julie Kniazeff , Laurent Prézeau , Jiang-Feng Liu , Philippe Rondard
Molecular and Cellular Endocrinology, 2019, ⟨10.1016/j.mce.2019.02.019⟩
Journal articles hal-02396289v1
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Infiltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23

Maya Kansara , Kristian Thomson , Puiyi Pang , Aurélie Dutour , Lisa Mirabello
Cancer Discovery, 2019, 9 (11), pp.1511-1519. ⟨10.1158/2159-8290.CD-19-0154⟩
Journal articles hal-02398127v1
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Rearrangement of the transmembrane domain interfaces associated with the activation 1 of a GPCR hetero-oligomer 2 3

Li Xue , Qian Sun , Han Zhao , Xavier Rovira , Siyu Gai
Nature Communications, 2019, 10 (1), pp.2765. ⟨10.1038/s41467-019-10834-5⟩
Journal articles hal-02398123v1
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Non-classical ligand-independent regulation of Go protein by an orphan Class C GPCR

Mariana Hajj , Teresa de Vita , Claire Vol , Charlotte Renassia , Jean-Charles Bologna
Molecular Pharmacology, 2019, 96 (2), pp.233-246. ⟨10.1124/mol.118.113019⟩
Journal articles hal-02396282v1
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Context-Dependent Signaling of CXC Chemokine Receptor 4 and Atypical Chemokine Receptor 3

Joyce Heuninck , Cristina Perpiñá Viciano , Ali Işbilir , Birgit Caspar , Davide Capoferri
Molecular Pharmacology, 2019, 96 (6), pp.778-793. ⟨10.1124/mol.118.115477⟩
Journal articles hal-02389610v1
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THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein‐coupled receptors

Stephen Alexander , Arthur Christopoulos , Anthony P Davenport , Eamonn Kelly , Alistair Mathie
British Journal of Pharmacology, 2019, 176 (S1), pp.S21-S141. ⟨10.1111/bph.14748⟩
Journal articles hal-02388696v1
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LSP5-2157 a new inhibitor of vesicular glutamate transporters

Odile Poirel , Lauren E Mamer , Melissa A Herman , Marie Arnulf-Kempcke , Myriam Kervern
Neuropharmacology, 2019, 164, pp.107902. ⟨10.1016/j.neuropharm.2019.107902⟩
Journal articles hal-03043497v1
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Allosteric interactions between GABA B1 subunits control orthosteric binding sites occupancy within GABA B oligomers

Gregory D Stewart , Laetitia Comps-Agrar , Lenea Blanc Nørskov-Lauritsen , Jean-Philippe Pin , Julie Kniazeff
Neuropharmacology, 2018, 136, pp.92-101. ⟨10.1016/j.neuropharm.2017.12.042⟩
Journal articles hal-02398132v1
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Oligomerization of a G protein-coupled receptor in neurons controlled by its structural dynamics

Thor C Møller , Jérôme Hottin , Caroline Clerté , Jurriaan M. Zwier , Thierry Durroux
Scientific Reports, 2018, 8 (1), ⟨10.1038/s41598-018-28682-6⟩
Journal articles hal-02398134v1

Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice

Cyril Rivat , Chamroeun Sar , Ilana Mechaly , Jean-Philippe Leyris , Lucie Diouloufet
Nature Communications, 2018, 9 (1), ⟨10.1038/s41467-018-03496-2⟩
Journal articles hal-03412426v1
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Direct coupling of detergent purified human mGlu5 receptor to the heterotrimeric G proteins Gq and Gs

Chady Nasrallah , Karine Rottier , Romain Marcellin , Vincent Compan , J. Font
Scientific Reports, 2018, 8 (1), pp.4407. ⟨10.1038/s41598-018-22729-4⟩
Journal articles hal-02073194v1
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Dynamic modulation of inflammatory pain-related affective and sensory symptoms by optical control of amygdala metabotropic glutamate receptor 4

Charleine Zussy , X. Gomez-Santacana , Xavier Rovira , Dimitri de Bundel , S. Ferrazzo
Molecular Psychiatry, 2018, 23 (3), pp.509-520. ⟨10.1038/mp.2016.223⟩
Journal articles hal-02073218v1
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Inhibition of neuronal FLT3 receptor tyrosine kinase alleviates peripheral neuropathic pain in mice