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Proc. Natl. Acad. Sci. USA, January 26, 2015 | doi: 10.1073/pnas.1410138112 PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission

Abstract

Ji Seung Ko^a,1, Gopal Pramanik^b,c,1, Ji Won Um^a,1, Ji Seon Shim^d, Dongmin Lee^e, Kee Hun Kim^f, Gug-Young Chung^a, Giuseppe Condomitti^g,h, Ho Min Kim^f, Hyun Kim^e, Joris de Wit^g,h, Kang-Sik Park^d, Katsuhiko Tabuchi^b,c,i, and Jaewon Ko^a,j,2

^aDepartment of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Korea;
^bDepartment of Molecular and Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan;
^cNational Institute for Physiological Sciences, The Graduate University for Advanced Studies, Okazaki 444-8787, Japan;
^dDepartment of Physiology, Kyung Hee University School of Medicine, Seoul 130-701, Korea;
^eDepartment of Anatomy and Division of Brain Korea 21 Biomedical Science, College of Medicine, Korea University, Seoul 136-705, Korea;
^fGraduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea;
^gVIB Center for the Biology of Disease, 3000 Leuven, Belgium;
^hCenter for Human Genetics, KU Leuven, 3000 Leuven, Belgium;
ⁱPrecursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan; and
^jDepartment of Psychiatry, Yonsei University College of Medicine, Seoul 120-751, Korea

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.

PTPσ, glypican, LRRTM4, synaptic cell adhesion, heparan sulfate

¹J.S.K., G.P., and J.W.U. contributed equally to this work.
²To whom correspondence should be addressed.

Author contributions: J.K. designed research; J.S.K., G.P., J.W.U., J.S.S., D.L., K.H.K., and G.C. performed research; G.-Y.C. and J.d.W. contributed new reagents/analytic tools; J.S.K., G.P., J.W.U., J.S.S., K.H.K., H.M.K., H.K., J.d.W., K.-S.P., K.T., and J.K. analyzed data; and J.S.K., J.W.U., and J.K. wrote the paper.

논문정보

형식Research article
게재일2015년 01월 (BRIC 등록일 2015-01-28)
연구진국내(교신)+국외 연구진
분야 생명과학 > 신경생물학

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