Team Philippe RONDARD

Neuroreceptors, dynamics and functions

Philippe Rondard
DR1, Inserm

The team has an extensive experience in neuropharmacology and the study of G protein-coupled receptors (GPCRs), which are the target of over 30% of all drugs. Our team has made important discoveries in the molecular pharmacology of two types of receptors, the glutamate receptor (mGlu) and the GABA-B receptor, which are the targets of two major neurotransmitters, glutamate and GABA respectively. The study of their molecular mechanisms using innovative biophysical and biochemical techniques has led to the discovery of novel allosteric modulators with important applications for neurological and psychiatric diseases.

mGlu and GABA-B receptors are complex G protein-coupled receptors that function as homodimers or heterodimers. They are also capable of forming complexes with other proteins, including membrane proteins, to modulate their activity in vivo. It is important to better understand the molecular and structural basis of these complexes and their dynamics, in particular to develop new molecules of therapeutic interest in the field of neurological and psychiatric diseases.

The team’s research project has four specific objectives:

1 – To study the molecular and structural basis of mGlu receptors and the complexes they form with other membrane partners, using biophysical and structural approaches (cryo-electron microscopy, analysis of conformational dynamics at the single-molecule scale using the Förster-type resonance energy transfer (FRET) techniques).

2- To develop methods and tools for studying mGlu and GABA-B receptors in vitro and in their native environment. The preferred methods are biosensors based on Förster-type resonance energy transfer (FRET, HTRFÒ) or bioluminescence (BRET) technologies. The tools developed are specific ligands, small molecules or camelid antibodies (nanobodies), and some of them can be controlled by light.

3- To study the complexes formed by mGlu receptors and their dynamics in their native environment. The aim is to identify functional complexes in the brain, such as the heterodimeric mGlu receptors recently discovered by the team. And to understand the physiological importance of these complexes for neuronal and brain function. The tools described above are used.

4- To develop nanobodies targeting mGlu receptors as innovative immunotherapies for the treatment of brain diseases, in particular schizophrenia.

The team studies the molecular pharmacology of mGlu and GABA-B receptors, from their structure and activation mechanism, pharmacology and signaling, to the development of innovative new ligands (camelid nanobodies and photoactivatable compounds) and their applications in several models of brain diseases.

Team leader
Philippe
Rondard
DR1, Inserm
  IGF Nord 223
  04 34 35 92 78
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Researchers
Anais
Menny
CRCN, CNRS
  IGF Nord 209b
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Jean-Philippe
Pin
DRCE, CNRS
  IGF Nord 223
  04 34 35 92 89
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Laurent
Prezeau
DR2, CNRS
  IGF Nord 221a
  04 34 35 93 07
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Jon Ander
Santas Martin
Accueil scientifique, CNRS
  IGF Nord 223
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Technicians and engineers
Isabelle
Brabet
IEHC, CNRS
  IGF Nord 219
  04 34 35 93 13
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Séverine
Diem
IECN, CNRS
  IGF Nord 221a
  04 34 35 93 07
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Postdoctoral researchers and doctoral students
Ugo
Alenda
Doctorant(e), UM
  IGF Nord 223
  04 34 35 93 07
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Marta
Cimadevila
Chercheur CDD, CNRS
  IGF Nord 215a
  04 34 35 93 07
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Anaïs
Djebara
Chercheur CDD, CNRS
  IGF Nord 221a
  04 34 35 93 07
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Nour
Fayad
Chercheur CDD, CNRS
  IGF Nord 223
  04 34 35 92 78
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Marine
Hoscar
Doctorant(e), UM
  IGF Nord 221a
  04 34 35 92 78
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Elise
Jacquier
Chercheur CDD, CNRS
  IGF Nord 209b
  04 34 35 93 07
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Pierre André
Lafon
Chercheur CDD, CNRS
  IGF Nord 209b
  04 34 35 92 89
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Yen-Ling
Lian
Chercheur CDD, CNRS
  IGF Nord 223
  04 34 35 92 89
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Junke
Liu
Chercheur CDD, CNRS
  IGF Nord 216a
  04 34 35 92 63
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Jiyong
Meng
Chercheur CDD, CNRS
  IGF Nord 215a
  04 34 35 92 78
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Clément
Peyron
Doctorant(e), Autre
  IGF Nord 215b
  04 34 35 92 78
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Léo
Pion
Chercheur CDD, Inserm
  IGF Nord 215b
  04 34 35 92 78
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Pierre
Prieu-Serandon
Doctorant(e), UM
  IGF Nord 223
  04 34 35 93 07
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Fixed term contract technicians and engineers
Célia
Algros
IE CDD, CNRS
  IGF Nord 221a
  04 34 35 92 89
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Célia
Camberlin
IE CDD, CNRS
  IGF Nord 216a
  04 34 35 92 63
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David
Lequen
IE CDD, CNRS
  IGF Nord 223
  04 34 35 92 78
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Imane
Maghni
IE CDD, CNRS
  IGF Nord 223
  04 34 35 92 78
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Cyrielle
Vial
IECN CDD, CNRS
  IGF Nord 209b
  04 34 35 92 89
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Trainees
Zélie
Chardonnay
Master 2, CNRS
  IGF Nord 215b
  04 34 35 92 78
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Célia
Sanie
Master 2, CNRS
  IGF Nord 221a
  04 34 35 93 07
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  • Xu C, Zhou Y, Liu Y, Lin L, Liu P, Wang X, Xu Z, Pin JP*, Rondard P*, Liu J* (2024). Specific pharmacological and Gi/o protein coupling properties of native GPCRs in neurons. Nat Comm 2024 15(1) :1990. doi: 10.1038/s41467-024-46177-z. PMID: 38443355 * Co-corresponding author.
  • Lecat-Guillet N, Quast RB, Liu H, Moeller TC, Rovira X, Soldevila S, Lamarque L, Trinquet E, Liu J, Pin JP, Rondard P*, Margeat E*. Concerted conformational changes control metabotropic glutamate receptor activity. Sci Adv 2023 9 (22) :eadf1378. doi: 10.1126/sciadv.adf1378. PMID: 37267369 * Co-corresponding author.
  • Meng J, Xu C, Lafon PA, Roux S, Mathieu M, Zhou R, Scholler P, Blanc E, Becker JAJ, Le Merrer J, González-Maeso J, Chames P, Liu J*, Pin JP*, Rondard P*. Optical biosensors of native membrane protein complexes reveal a high proportion of mGlu heterodimers in the brain. Nat Chem Biol 2022, 18, 894-903. doi: 10.1038/s41589-022-01050-2. PMID: 35681029 * Co-corresponding author.
  • Liu J, Tang H, Xu C, Zhou S, Zhu X, Li Y, Prézeau L, Xu T, Pin JP*, Rondard P*, Ji W*, Liu J* (2022) Biased signaling due to oligomerization of a G protein-coupled receptor. Nat Comm 2022 13, 6365.  doi: 10.1038/s41467-022-34056-4. PMID: 36289206 * Co-corresponding author.
  • Haubrich J, Font J, Goupil-Lamy A, Scholler P, Nevoltris D, Acher F, Chames P, Rondard P, Prézeau L*, Pin J-P*. A nanobody activating metabotropic glutamate receptor 4 discriminates between homo- and heterodimers. Proc Natl Acad Sci U S A 2021 118 (33):e2105848118. doi: 10.1073/pnas.2105848118. PMID: 34385321* Co-corresponding author.
  • Cao AM, Quast RB, Fatemi F, Rondard P, Pin JP*, Margeat E* (2021) Allosteric modulators enhance agonist efficacy by increasing the residence time of a GPCR in the active state. Nat Comm 2021 12 (1):5426. doi: 10.1038/s41467-021-25620-5. PMID: 34521824* Co-corresponding author.
  • Liu H, Yi P, Zhao W, Wu Y, Acher F, Pin JP*, Liu J*, Rondard P. Illuminating the allosteric modulation of the calcium sensing receptor. Proc Natl Acad Sci U S A 2020 117 (35) 21711-21722. doi: 10.1073/pnas.1922231117. PMID: 32817431 * Co-corresponding author.
  • Xue L, Sun Q, Zhao H, Rovira X, Gai S, He Q, Pin JP*, Liu J*, Rondard P. Rearrangement of the transmembrane domain interfaces associated with the activation of a GPCR hetero-oligomer. Nat Commun 2019 10, 2765. doi: 10.1038/s41467-019-10834-5. PMID: 31235691 * Co-corresponding author.
  • Scholler P, Nevoltris D, De Blundel D, Bossi S, Moreno D, Rovira X, Møller TC, El-Moustaine D, Mathieu M, Blanc E, McLean H, Dupuis E, Mathis G, Trinquet E, Daniel H, Valjent E, Baty D, Chames P, Rondard P*, Pin JP*. Allosteric nanobodies uncover a role of hippocampal mGlu2 receptor homodimers in contextual fear consolidation. Nat Commun 2017 8 (1):1967. doi: 10.1038/s41467-017-01489-1. PMID: 29213077 * Co-corresponding author.
  • Scholler P, Moreno D, Lecat-Guillet N, Doumazane E, Monnier C, Charrier-Savournin F, Fabre L, Chouvet C, Soldevila S, Lamarque L, Donsimoni G, Roux T, Zwier JM, Trinquet E, Rondard P*, Pin JP*. HTS-compatible FRET-based conformational sensors clarify membrane receptor activation. Nat Chem Biol 2017 13, 372-380. doi: 10.1038/nchembio.2286. PMID: 28135236 * Co-corresponding author

GPCR complexes

Principal investigator
Anaïs MENNY

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Development of methods and tools for studying GPCRs

Principal investigator
Jean-Philippe PIN

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Complexes of mGlu receptors and their dynamics in native environment

Principal investigator
Laurent PREZEAU

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Nanobodies targeting mGlu receptors as innovative immunotherapy for the treatment of brain diseases

Principal investigator
Philippe RONDARD

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Revvity Cisbio
Codolet, France

Emmanuel Margeat
Centre de Biologie Structurale (CBS), Montpellier, France

Francine Acher
Université Paris Cité, Paris, France

Patrick Chames
Aix-Marseille Université, France

Jianfeng Liu
Huazhong University of Science and Technology (HUST), Wuhan, China

Amadeu Llebaria
University of Barcelona, Barcelona, Spain

PhD students

• Alexandre Bouyssou (Genentech, USA)
• Laetitia Comps-Agrar (Genentech, USA)
• Mélanie Da Silva
• Damien Maurel
• Carine Monnier
• Mathieu Oosterlaken
• Marie-Laure Rives
• Pauline Scholler (Revvity)

Post-doctoral fellows

• Fanny Dubois
• Driss El Moustaine
• Nathalie Lecat-Guillet (Revvity)
• Oualid Sbai
• Li Xue (Shanghai Jiao Tong University School of Medicine, Shanghai, China)

Engineers

• Emilie Blanc
• Michaël Mathieu (Revvity)
• Jessica Monnic (Mabqi)
• Roxane Perrin
• Salomé Roux