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 RIS Download
Amino Acid Sequence | Animals | Blotting, Western | Brain | Carrier Proteins | HEK293 Cells | Homer Scaffolding Proteins | 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