Preso1 dynamically regulates group I metabotropic glutamate receptors


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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Figure 1: Preso1 binds to Homer and localizes to the postsynaptic density.
Figure 2: Preso1 binds to the mGluR5 C terminus by means of its FERM domain.
Figure 3: Preso1 enhances mGluR5 phosphorylation and Homer–mGluR5 binding, and inhibits group I mGluR coupling to voltage-gated Ca2+ channels.
Figure 4: Preso1 binds proline-directed kinases and enhances kinase-mGluR5 binding.
Figure 5: Preso1 is required for activity-dependent increase of mGluR5 phosphorylation and Homer binding.
Figure 6: Increased pain response to formalin or complete Freund's adjuvant in Preso1−/− mice.
Figure 7: Enhanced group I mGluR-mediated calcium response in the spinal cord neurons of Preso1−/− mice.


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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.).

Author information




J.-H.H. designed, performed and analyzed experiments included in Figures 1, 2, 3, 4, 5, 6, 7 and Supplementary Figures 1–6 and 8, and wrote a first draft of the manuscript. L.Y. performed and analyzed experiments in Figures 1 and 2 and Supplementary Figure 4. P.J.K. performed and analyzed electrophysiology experiments in Figure 3. C.G.M. generated and identified the phospho-mGluR antibody in Supplementary Figure 4. P.R.B. performed the yeast-two hybrid screen that identified Preso1 as a Homer binding protein. J.T. and B.X. cloned Preso1 and did initial characterizations. S.Y. generated the Preso1 antibody. R.S.P. performed the experiments in Figure 1. Z.L. performed and analyzed experiments in Supplementary Figure 7. P.-W.Z. generated Grm5R/R mice. J.M.P. performed electrophysiological experiments. X.D. provided intellectual input and technical support on the behavioral experiments and dorsal root ganglion neuron recordings. B.X. generated Preso1 antibodies, designed and performed experiments in Figure 1 and provided intellectual input and technical support for Preso1−/− mouse generation. P.F.W. supervised the overall project, designed experiments and wrote the final version of the manuscript.

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Correspondence to Paul F Worley.

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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).

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