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- Title
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
- 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.
- Publication
Nature neuroscience, 2012, Vol 15, Issue 6, p836
- ISSN
1546-1726
- Publication type
Journal Article
- DOI
10.1038/nn.3103