Preso1 dynamically regulates group I metabotropic glutamate receptors.
- Authors
- 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.