title: Preso1 dynamically regulates group I metabotropic glutamate receptors.
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.
authors.affiliation: Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Jia-Hua
authors.initials: JH
authors.lastname: Hu
authors.forename: Linlin
authors.initials: L
authors.lastname: Yang
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kammermeier
authors.forename: Chester G
authors.initials: CG
authors.lastname: Moore
authors.forename: Paul R
authors.initials: PR
authors.lastname: Brakeman
authors.forename: Jiancheng
authors.initials: J
authors.lastname: Tu
authors.forename: Shouyang
authors.initials: S
authors.lastname: Yu
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Petralia
authors.forename: Zhe
authors.initials: Z
authors.lastname: Li
authors.forename: Ping-Wu
authors.initials: PW
authors.lastname: Zhang
authors.forename: Joo Min
authors.initials: JM
authors.lastname: Park
authors.forename: Xinzhong
authors.initials: X
authors.lastname: Dong
authors.forename: Bo
authors.initials: B
authors.lastname: Xiao
authors.forename: Paul F
authors.initials: PF
authors.lastname: Worley
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D000072233:Homer Scaffolding Proteins; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D057907:Post-Synaptic Density; D038461:Proline-Directed Protein Kinases / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection
chemical_list: D002352:Carrier Proteins; D000072233:Homer Scaffolding Proteins; D018094:Receptors, Metabotropic Glutamate; D038461:Proline-Directed Protein Kinases