Neuroreceptors, Dynamics and Function

 Jean-Philippe PIN

 IGF - UMR 5203/U 661

 141, rue de la Cardonille, 34396 Montpellier

Phone: +33 4 34 35 92 99

Email: jean-philippe.pin@igf.cnrs.fr

Website

Our work focuses on the molecular dynamics of the G protein coupled receptors activated by the two main neurotransmitters, Glutamate and GABA. Three main aspects are being studied:

1- the structural dynamics of these complex dimeric receptors. Such studies are carried out using state of the art FRET and single molecule technologies in living cells, based on original labeling techniques; as well as using purified and reconstituted proteins.

2- The dynamics of proteins complexes associated with these receptors, as identified by mass spectrometry, including intracellular partners as well as other receptors.

3- The development of new tools (selective ligands, peptide competitors, nanobodies, viral vectors, mutant mice) to decipher the therapeutic potential of targeting these receptors for the treatment of pain and Parkinson's disease.

Keywords: G protein coupled receptors – Glutamate & GABA – Structural dynamics – neurodegenerative and psychiatric diseases

Main publications

• Monnier C, Tu H, Bourrier E, Vol C, Lamarque L, Trinquet E, Pin J-P, Rondard P (2011) Transactivation between 7TM domains: implication in heterodimeric GABAB receptor activation EMBO J 30:32-42.
• Huang S, Cao J, Jiang M, Labesse G, Liu J, Pin J-P, Rondard P (2011) Interdomain movements in metabotropic glutamate receptor activation. Proc Natl Acad Sci (USA) 108:15480-15485.
• Comps-Agrar L, Kniazeff J, Nørskov-Lauritsen L, Maurel D, Gassmann M, Gregor N, Prézeau L, Bettler B, Durroux T, Trinquet E, Pin J-P (2011) The oligomeric state sets GABAB receptor signalling efficacy. EMBO J 30:2336-2349.
• Albizu L, Cottet M, Stoev S, Seyer R, Brabet I, Roux T, Bazin H, Bourrier E, Lamarque L, Breton C, Rives M, Kralikova M, Newman AH, Javitch JA, Trinquet E, Manning M, Pin J-P, Mouillac B, Durroux T (2010) Time-resolved FRET between ligands bound on asymmetric G protein-coupled receptor reveals oligomers in native tissues. Nat Chem Biol 6:587-594.
• Rives ML, Vol C, Fukazawa Y, Tinel N, Trinquet E, Ayoub MA, Shigemoto R, Pin JP, Prezeau L (2009) Crosstalk between GABA(B) and mGlu1a receptors reveals new insight into GPCR signal integration. EMBO J 28:2195-2208.
• Rondard P, Huang S, Monnier C, Tu H, Blanchard B, Oueslati N, Malhaire F, Li Y, Maurel D, Trinquet E, Labesse G, Pin* J-P, Liu J (2008) Functioning of the dimeric GABAB receptor extracellular domain revealed by glycan wedge scanning. EMBO J 27:1321-1332.
• Maurel D, Comps-Agrar L, Brock C, Rives M-L, Bourrier E, Ayoub MA, Bazin H, Tinel N, Durroux T, Prézeau L, Trinquet E, Pin J-P (2008) Cell surface protein-protein interaction analysis with combined time-resolved FRET and snap-tag technologies: application to GPCR oligomerization. Nat Meth 5:561-567.
• Hlavackova V, Goudet C, Kniazeff J, Zikova A, Maurel D, Vol C, Trojanova J, Prézeau L, Pin* J-P, Blahos J (2005) Evidence for a single heptahelical domain being turned on upon activation of a dimeric GPCR. EMBO J 24:499-509.
• Kniazeff J, Bessis A-S, Maurel D, Ansanay H, Prezeau L, Pin J-P (2004) Closed state of both binding domains of homodimeric mGlu receptors is required for full activity. Nat Str Mol Biol 11:706-713.
• Goudet C, Gaven F, Kniazeff J, Vol C, Liu J, Cohen-Gonsaud M, Acher F, Prézeau L, Pin JP (2004) Heptahelical domain of metabotropic glutamate receptor 5 behaves like rhodopsin-like receptors. Proc Natl Acad Sci (USA) 101:378-383.