New Modes of GPCR Signalling

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ABSTRACT mGlu Receptors : Complex Allosteric Machines to Tune Up Synaptic Transmission Philippe Rondard1, Etienne Doumazane1, Pauline Scholler1, Eric Trinquet2, Sébastien Granier1 & Jean-Philippe Pin1 1 CNRS UMR5203, INSERM U661, University of Montpellier, Department of Molecular Pharmacology, Institute of Functional Genomics, Montpellier, France. 2 CisBio International, Bagnols/Cèze , France The G-protein coupled receptors activated by the neurotransmitter glutamate (mGluRs) are made up of two subunits covalently linked by a disulfide bridge. Each protomer comprises an extracellular domain that binds agonists and a transmembrane heptahelical domain responsible for G-protein activation. The general organization of mGluRs at the cell surface, whether they are limited to dimers, or organized into high-order oligomers, as well as the functioning of the dimeric receptors remain unclear. Here, we first examined whether mGluRs can assemble into heteromeric complexes. To that aim we describe a new approach enabling the specific labeling of two cell surface proteins carrying SNAP- or CLIP-tags, with two distinct fluorophores compatible with time-resolved FRET. This approach allowed us to quantify both homomeric and heteromeric populations. Our data revealed that some, but not all pairs of mGluRs can indeed form heteromeric entities, and this is further supported by biochemical analysis and functional complementation studies. By FRET competition and saturation analysis, we show that these complexes are limited to heterodimers. In addition to describing a new way to analyze cell surface receptor complexes, our data reveal a new possible level of complexity within the mGluR family. Second, whereas dimerization of the extracellular domains is essential for the activation, it is not known if the function of the transmembrane domains also depends on dimerization. To address this question, we analyzed the G protein coupling of purified mGluR membrane domain reconstituted into phospholipid bilayer nanodisc with a controlled stoichiometry: one or two protomers per disc. Nanodiscs containing only one mGluR membrane domain are able to activate G proteins in response to a positive allosteric modulator, demonstrating that monomeric mGluR membrane domain can fold and function independently from the rest of the receptor. These results suggest that dimer requirement in mGluR function originate from an obligate communication between the extracellular and transmembrane domains in the receptor for activation by glutamate, rather than a necessity for specific association between the two membrane domains.
INVITED SPEAKER’S INFO Prof. Denise Montell PhD, Professor, Director, Department of Biological Chemistry, Center for Cell Dynamics Johns Hopkins School of Medicine, 855 North Wolfe Street, Baltimore, MD 21205-2185 Phone: (410) 614-2016 Fax: (410) 614-8375 Email: dmontell@jhmi.edu Education and Training 1979-1983 B. A.,University of California, San Diego, Biochemistry and Cell Biology 1983-1988 Ph.D., Stanford University, Neurosciences 1988-1990 Postdoctoral studies, , Carnegie Institution, Developmental Genetics Professional Experience 1990-1992 Staff Associate, Carnegie Institution, Department of Embryology 1992-1998 Assistant Professor, Department of Biological Chemistry Johns Hopkins University School of Medicine 1998-2002 Associate Professor, Department of Biological Chemistry Johns Hopkins University School of Medicine 2002- Professor, Department of Biological Chemistr Johns Hopkins University School of Medicine 1999- Director, Graduate Program in Biological Chemistry 2006- Director, Center for Cell Dynamics. Selected Publications 1. Geisbrecht, E. and Montell, D. J. (2002) Requirement for Myosin VI in E-cadherin-mediated border cell migration, Nature Cell Biol 4, 616-620. Cover photo. 2. Montell, D. J. (2003) Border cell migration: the race is on. Nature Reviews Molecular Cell Biology 4, 13-24. 3. Naora, H. and Montell, DJ. (2005) Ovarian cancer metastasis: Integrating insights from disparate model organisms. Nature Reviews Cancer, 5, 355-66. 4. Jang, A. C.-C., Chang, Y.-C., Bai, J. and Montell, D.J. (2009) Border cell migration requires integration of spatial and temporal signals by the BTB protein Abrupt. Nature Cell Biol 11:569-79. 5. Wang, X., He, L., Wu, Y., Hahn, K. and Montell, D. J. Light-mediated activation reveals a key role for Rac in collective guidance of cell movement in vivo, Nature Cell Biol, in press. 6. Montell, D. J., Keshishian, H., and Spradling, A. C. (1991) Laser ablation studies of the role of the Drosophila oocyte nucleus in pattern formation. Science 254,
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