Preso1 dynamically regulates group i metabotropic glutamate receptors

Jia Hua Hu, Linlin Yang, Paul J. Kammermeier, Chester G. Moore, Paul R. Brakeman, Jiancheng Tu, Shouyang Yu, Ronald S. Petralia, Zhe Li, Ping Wu Zhang, Joo Min Park, Xinzhong Dong, Bo Xiao, Paul F. Worley

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)836-844
Number of pages9
JournalNature neuroscience
Issue number6
StatePublished - Jun 2012

ASJC Scopus subject areas

  • Neuroscience(all)


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