Direct interaction enables cross-talk between ionotropic and group I metabotropic glutamate receptors.
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.
Perroy
Julie
J
Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Universités de Montpellier 1 and 2, Montpellier 34094, France.
Raynaud
Fabrice
F
Homburger
Vincent
V
Rousset
Marie-Claude
MC
Telley
Ludovic
L
Bockaert
Joël
J
Fagni
Laurent
L
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
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