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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.

Pubmed ID: 22561452


  • Hu JH
  • Yang L
  • Kammermeier PJ
  • Moore CG
  • Brakeman PR
  • Tu J
  • Yu S
  • Petralia RS
  • Li Z
  • Zhang PW
  • Park JM
  • Dong X
  • Xiao B
  • Worley PF


Nature neuroscience

Publication Data

June 4, 2012

Associated Grants

  • Agency: NIDA NIH HHS, Id: DA010309
  • Agency: NIGMS NIH HHS, Id: GM087369
  • Agency: NIMH NIH HHS, Id: MH084020
  • Agency: NINDS NIH HHS, Id: NS050274
  • Agency: NINDS NIH HHS, Id: NS054791
  • Agency: Intramural NIH HHS, Id: ZIA DC000003-23

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Blotting, Western
  • Brain
  • Carrier Proteins
  • HEK293 Cells
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • Male
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Neurons
  • Phosphorylation
  • Post-Synaptic Density
  • Proline-Directed Protein Kinases
  • Protein Binding
  • Protein Structure, Tertiary
  • Rats
  • Rats, Wistar
  • Receptors, Metabotropic Glutamate
  • Signal Transduction
  • Transfection