Group I metabotropic glutamate receptors (mGluRs), including mGluR1 and mGluR5, are G protein–coupled receptors (GPCRs) that are expressed at excitatory synapses in brain and spinal cord. GPCRs are often negatively regulated by specific G protein–coupled receptor kinases and subsequent binding of arrestin-like molecules. Here we demonstrate an alternative mechanism in which group I mGluRs are negatively regulated by proline-directed kinases that phosphorylate the binding site for the adaptor protein Homer, and thereby enhance mGluR–Homer binding to reduce signaling. This mechanism is dependent on a multidomain scaffolding protein, Preso1, that binds mGluR, Homer and proline-directed kinases and that is required for their phosphorylation of mGluR at the Homer binding site. Genetic ablation of Preso1 prevents dynamic phosphorylation of mGluR5, and Preso1−/− mice exhibit sustained, mGluR5-dependent inflammatory pain that is linked to enhanced mGluR signaling. Preso1 creates a microdomain for proline-directed kinases with broad substrate specificity to phosphorylate mGluR and to mediate negative regulation.
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We thank J. Roder of University of Toronto for Grm5−/− mice, J. Worley for help with behavioral experiments and Y.-X. Wang for help with the immunogold. This work was supported by US National Institutes of Health grants from the National Institute on Drug Abuse (DA010309), National Institute of Mental Health (MH084020) and National Institute of Neurological Disorders and Stroke (NS050274 (P.F.W.); NS054791 and GM087369 (X.D.)); National 973 Basic Research Program of China (20009CB941400; B.X.); and the National Institute on Deafness and Other Communication Disorders Intramural Research Program (R.S.P.).
The authors declare no competing financial interests.
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Hu, JH., Yang, L., Kammermeier, P. et al. Preso1 dynamically regulates group I metabotropic glutamate receptors. Nat Neurosci 15, 836–844 (2012). https://doi.org/10.1038/nn.3103
International Union of Basic and Clinical Pharmacology. CXI. Pharmacology, Signaling, and Physiology of Metabotropic Glutamate Receptors
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