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Preso1 dynamically regulates group I metabotropic glutamate receptors.

Authors
  • Hu, Jia-Hua
  • Yang, Linlin
  • Kammermeier, Paul J
  • Moore, Chester G
  • Brakeman, Paul R
  • Tu, Jiancheng
  • Yu, Shouyang
  • Petralia, Ronald S
  • Li, Zhe
  • Zhang, Ping-Wu
  • Park, Joo Min
  • Dong, Xinzhong
  • Xiao, Bo
  • Worley, Paul F
Type
Published Article
Journal
Nature Neuroscience
Publisher
Springer Nature
Publication Date
Jun 01, 2012
Volume
15
Issue
6
Pages
836–844
Identifiers
DOI: 10.1038/nn.3103
PMID: 22561452
Source
Medline
License
Unknown

Abstract

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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