title: Direct interaction enables cross-talk between ionotropic and group I metabotropic glutamate receptors.
abstract: Functional interplay between ionotropic and metabotropic receptors frequently involves complex intracellular signaling cascades. The group I metabotropic glutamate receptor mGlu5a co-clusters with the ionotropic N-methyl-d-aspartate (NMDA) receptor in hippocampal neurons. In this study, we report that a more direct cross-talk can exist between these types of receptors. Using bioluminescence resonance energy transfer in living HEK293 cells, we demonstrate that mGlu5a and NMDA receptor clustering reflects the existence of direct physical interactions. Consequently, the mGlu5a receptor decreased NMDA receptor current, and reciprocally, the NMDA receptor strongly reduced the ability of the mGlu5a receptor to release intracellular calcium. We show that deletion of the C terminus of the mGlu5a receptor abolished both its interaction with the NMDA receptor and reciprocal inhibition of the receptors. This direct functional interaction implies a higher degree of target-effector specificity, timing, and subcellular localization of signaling than could ever be predicted with complex signaling pathways.
authors.affiliation: Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Universités de Montpellier 1 and 2, Montpellier 34094, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Perroy
authors.forename: Fabrice
authors.initials: F
authors.lastname: Raynaud
authors.forename: Vincent
authors.initials: V
authors.lastname: Homburger
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Rousset
authors.forename: Ludovic
authors.initials: L
authors.lastname: Telley
authors.forename: Joël
authors.initials: J
authors.lastname: Bockaert
authors.forename: Laurent
authors.initials: L
authors.lastname: Fagni
mesh_terms: D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004735:Energy Transfer; D019204:GTP-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008164:Luminescent Proteins / Q000737:chemistry; D008954:Models, Biological; D017434:Protein Structure, Tertiary; D064529:Receptor, Metabotropic Glutamate 5; D018092:Kainic Acid Receptors / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D002118:Calcium; D019204:GTP-Binding Proteins; D008164:Luminescent Proteins; D064529:Receptor, Metabotropic Glutamate 5; D018092:Kainic Acid Receptors; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate