title: PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission.
abstract: Leukocyte common antigen-related receptor protein tyrosine phosphatases--comprising LAR, PTPδ, and PTPσ--are synaptic adhesion molecules that organize synapse development. Here, we identify glypican 4 (GPC-4) as a ligand for PTPσ. GPC-4 showed strong (nanomolar) affinity and heparan sulfate (HS)-dependent interaction with the Ig domains of PTPσ. PTPσ bound only to proteolytically cleaved GPC-4 and formed additional complex with leucine-rich repeat transmembrane protein 4 (LRRTM4) in rat brains. Moreover, single knockdown (KD) of PTPσ, but not LAR, in cultured neurons significantly reduced the synaptogenic activity of LRRTM4, a postsynaptic ligand of GPC-4, in heterologous synapse-formation assays. Finally, PTPσ KD dramatically decreased both the frequency and amplitude of excitatory synaptic transmission. This effect was reversed by wild-type PTPσ, but not by a HS-binding-defective PTPσ mutant. Our results collectively suggest that presynaptic PTPσ, together with GPC-4, acts in a HS-dependent manner to maintain excitatory synapse development and function.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea;
authors.forename: Ji Seung
authors.initials: JS
authors.lastname: Ko
authors.affiliation: Department of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan; National Institute for Physiological Sciences, The Graduate University for Advanced Studies, Okazaki 444-8787, Japan;
authors.forename: Gopal
authors.initials: G
authors.lastname: Pramanik
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea;
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Um
authors.affiliation: Department of Physiology, Kyung Hee University School of Medicine, Seoul 130-701, Korea;
authors.forename: Ji Seon
authors.initials: JS
authors.lastname: Shim
authors.affiliation: Department of Anatomy and Division of Brain Korea 21 Biomedical Science, College of Medicine, Korea University, Seoul 136-705, Korea;
authors.forename: Dongmin
authors.initials: D
authors.lastname: Lee
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea;
authors.forename: Kee Hun
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea;
authors.forename: Gug-Young
authors.initials: GY
authors.lastname: Chung
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium;
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Condomitti
authors.affiliation: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea;
authors.forename: Ho Min
authors.initials: HM
authors.lastname: Kim
authors.affiliation: Department of Anatomy and Division of Brain Korea 21 Biomedical Science, College of Medicine, Korea University, Seoul 136-705, Korea;
authors.forename: Hyun
authors.initials: H
authors.lastname: Kim
authors.affiliation: VIB Center for the Biology of Disease, 3000 Leuven, Belgium; Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium;
authors.forename: Joris
authors.initials: J
authors.lastname: de Wit
authors.affiliation: Department of Physiology, Kyung Hee University School of Medicine, Seoul 130-701, Korea;
authors.forename: Kang-Sik
authors.initials: KS
authors.lastname: Park
authors.affiliation: Department of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan; National Institute for Physiological Sciences, The Graduate University for Advanced Studies, Okazaki 444-8787, Japan; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan; and.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Tabuchi
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea; Department of Psychiatry, Yonsei University College of Medicine, Seoul 120-751, Korea jaewonko@yonsei.ac.kr.
authors.forename: Jaewon
authors.initials: J
authors.lastname: Ko
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002846:Chromatography, Affinity; D002851:Chromatography, High Pressure Liquid; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors / Q000235:genetics; D053673:Glypicans / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D000090263:Leucine-Rich Repeat Proteins; D013058:Mass Spectrometry; D046912:Multiprotein Complexes / Q000378:metabolism*; D009841:Oligonucleotides / Q000235:genetics; D017729:Presynaptic Terminals / Q000502:physiology; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D053673:Glypicans; D006497:Heparan Sulfate; D000090263:Leucine-Rich Repeat Proteins; D046912:Multiprotein Complexes; D009841:Oligonucleotides; D011506:Proteins; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2
keywords: LRRTM4; PTPσ; glypican; heparan sulfate; synaptic cell adhesion