Dataset Information

PTP? 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, PTP?, and PTP?--are synaptic adhesion molecules that organize synapse development. Here, we identify glypican 4 (GPC-4) as a ligand for PTP?. GPC-4 showed strong (nanomolar) affinity and heparan sulfate (HS)-dependent interaction with the Ig domains of PTP?. PTP? 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 PTP?, 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, PTP? KD dramatically decreased both the frequency and amplitude of excitatory synaptic transmission. This effect was reversed by wild-type PTP?, but not by a HS-binding-defective PTP? mutant. Our results collectively suggest that presynaptic PTP?, together with GPC-4, acts in a HS-dependent manner to maintain excitatory synapse development and function.

SUBMITTER: Ko JS

PROVIDER: S-EPMC4330736 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission.

Ko Ji Seung JS Pramanik Gopal G Um Ji Won JW Shim Ji Seon JS Lee Dongmin D Kim Kee Hun KH Chung Gug-Young GY Condomitti Giuseppe G Kim Ho Min HM Kim Hyun H de Wit Joris J Park Kang-Sik KS Tabuchi Katsuhiko K Ko Jaewon J

Proceedings of the National Academy of Sciences of the United States of America 20150126 6

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. ...[more]

PMID: 25624497

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Project description:Leukocyte common antigen-receptor protein tyrosine phosphatases (LAR-RPTPs) are hub proteins that organize excitatory and inhibitory synapse development through binding to various extracellular ligands. Here, we report that knockdown (KD) of the LAR-RPTP family member PTP? reduced excitatory synapse number and transmission in cultured rat hippocampal neurons, whereas KD of PTP? produced comparable decreases at inhibitory synapses, in both cases without altering expression levels of interacting proteins. An extensive series of rescue experiments revealed that extracellular interactions of PTP? with Slitrks are important for excitatory synapse development. These experiments further showed that the intracellular D2 domain of PTP? is required for induction of heterologous synapse formation by Slitrk1 or TrkC, suggesting that interaction of LAR-RPTPs with distinct intracellular presynaptic proteins, drives presynaptic machinery assembly. Consistent with this, double-KD of liprin-?2 and -?3 or KD of PTP? substrates (N-cadherin and p250RhoGAP) in neurons inhibited Slitrk6-induced, PTP?-mediated heterologous synapse formation activity. We propose a synaptogenesis model in presynaptic neurons involving LAR-RPTP-organized retrograde signaling cascades, in which both extracellular and intracellular mechanisms are critical in orchestrating distinct synapse types.SIGNIFICANCE STATEMENT In this study, we sought to test the unproven hypothesis that PTP? and PTP? are required for excitatory and inhibitory synapse formation/transmission, respectively, in cultured hippocampal neurons, using knockdown-based loss-of-function analyses. We further performed extensive structure-function analyses, focusing on PTP?-mediated actions, to address the mechanisms of presynaptic assembly at excitatory synaptic sites. Using interdisciplinary approaches, we systematically applied a varied set of PTP? deletion variants, point mutants, and splice variants to demonstrate that both extracellular and intracellular mechanisms are involved in organizing presynaptic assembly. Strikingly, extracellular interactions of PTP? with heparan sulfates and Slitrks, intracellular interactions of PTP? with liprin-? and its associated proteins through the D2 domain, as well as distinct substrates are all critical.

Dataset Information

PTP? functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission.

Publications

PTPσ functions as a presynaptic receptor for the glypican-4/LRRTM4 complex and is essential for excitatory synaptic transmission.

Similar Datasets

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