title: Role of Spinophilin in Group I Metabotropic Glutamate Receptor Endocytosis, Signaling, and Synaptic Plasticity.
abstract: Activation of Group I metabotropic glutamate receptors (mGluRs) activates signaling cascades, resulting in calcium release from intracellular stores, ERK1/2 activation, and long term changes in synaptic activity that are implicated in learning, memory, and neurodegenerative diseases. As such, elucidating the molecular mechanisms underlying Group I mGluR signaling is important for understanding physiological responses initiated by the activation of these receptors. In the current study, we identify the multifunctional scaffolding protein spinophilin as a novel Group I mGluR-interacting protein. We demonstrate that spinophilin interacts with the C-terminal tail and second intracellular loop of Group I mGluRs. Furthermore, we show that interaction of spinophilin with Group I mGluRs attenuates receptor endocytosis and phosphorylation of ERK1/2, an effect that is dependent upon the interaction of spinophilin with the C-terminal PDZ binding motif encoded by Group I mGluRs. Spinophilin knock-out results in enhanced mGluR5 endocytosis as well as increased ERK1/2, AKT, and Ca(2+) signaling in primary cortical neurons. In addition, the loss of spinophilin expression results in impaired mGluR5-stimulated LTD. Our results indicate that spinophilin plays an important role in regulating the activity of Group I mGluRs as well as their influence on synaptic activity.
authors.affiliation: From the J. Allyn Taylor Centre for Cell Biology, Robarts Research Institute, London, Ontario N6A 3K7, Canada.
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Di Sebastiano
authors.affiliation: From the J. Allyn Taylor Centre for Cell Biology, Robarts Research Institute, London, Ontario N6A 3K7, Canada.
authors.forename: Sandra
authors.initials: S
authors.lastname: Fahim
authors.affiliation: the Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
authors.forename: Henry A
authors.initials: HA
authors.lastname: Dunn
authors.affiliation: From the J. Allyn Taylor Centre for Cell Biology, Robarts Research Institute, London, Ontario N6A 3K7, Canada.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Walther
authors.affiliation: the Departamento de Bioquimica e Imunologia, ICB, Universidade Federa de Minas Gerais, Belo Horizonte 31270-901, Brazil.
authors.forename: Fabiola M
authors.initials: FM
authors.lastname: Ribeiro
authors.affiliation: From the J. Allyn Taylor Centre for Cell Biology, Robarts Research Institute, London, Ontario N6A 3K7, Canada.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Cregan
authors.affiliation: the Leslie Dan Faculty of Pharmacy and Department of Pharmacology, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
authors.forename: Stephane
authors.initials: S
authors.lastname: Angers
authors.affiliation: the Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A 3K7, Canada, and.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schmid
authors.affiliation: the Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario N6A 3K7, Canada, and sferguso@uottawa.ca.
authors.forename: Stephen S G
authors.initials: SS
authors.lastname: Ferguson
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D004705:Endocytosis / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D000099273:Neurabins
chemical_list: D008840:Microfilament Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009419:Nerve Tissue Proteins; D051057:Proto-Oncogene Proteins c-akt; D018094:Receptors, Metabotropic Glutamate; D000099273:Neurabins; C535150:MAPK1 protein, human
keywords: calcium imaging; endocytosis; extracellular-signal-regulated kinase (ERK); glutamate receptor; receptor regulation