한빛사 논문
Abstract
1 National Creative Research Initiative Center for Synaptogenesis and Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea, 2 The Picower Institute for Learning and Memory, RIKEN-MIT Neuroscience Research Center, 3 Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, 4 Department of Physiology and Dental Research Institute, Seoul National University School of Dentistry, Seoul, Korea, 5 CNR Institute of Neuroscience and Department of Neurological Sciences, University of Milan, Milan, Italy, 6 Department of Anatomy and Division of Brain Korea 21 Biomedical Science, College of Medicine, Korea University, Seoul, Korea, 7 Department of Chemical and Systems Biology, Stanford University, Stanford, California, United States of America
Abstract
Long-term depression (LTD) is a long-lasting activity-dependent decrease in synaptic strength. NMDA receptor (NMDAR)–dependent LTD, an extensively studied form of LTD, involves the endocytosis of AMPA receptors (AMPARs) via protein dephosphorylation, but the underlying mechanism has remained unclear. We show here that a regulated interaction of the endocytic adaptor RalBP1 with two synaptic proteins, the small GTPase RalA and the postsynaptic scaffolding protein PSD-95, controls NMDAR-dependent AMPAR endocytosis during LTD. NMDAR activation stimulates RalA, which binds and translocates widespread RalBP1 to synapses. In addition, NMDAR activation dephosphorylates RalBP1, promoting the interaction of RalBP1 with PSD-95. These two regulated interactions are required for NMDAR-dependent AMPAR endocytosis and LTD and are sufficient to induce AMPAR endocytosis in the absence of NMDAR activation. RalA in the basal state, however, maintains surface AMPARs. We propose that NMDAR activation brings RalBP1 close to PSD-95 to promote the interaction of RalBP1-associated endocytic proteins with PSD-95-associated AMPARs. This suggests that scaffolding proteins at specialized cellular junctions can switch their function from maintenance to endocytosis of interacting membrane proteins in a regulated manner.Citation: Han K, Kim M-H, Seeburg D, Seo J, Verpelli C, et al. (2009) Regulated RalBP1 Binding to RalA and PSD-95 Controls AMPA Receptor Endocytosis and LTD. PLoS Biol 7(9): e1000187. doi:10.1371/journal.pbio.1000187
Academic Editor: Michael D. Ehlers, Duke University Medical Center, United States of America
Received: February 12, 2009; Accepted: July 30, 2009; Published: September 8, 2009
Copyright: © 2009 Han et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the Creative Research Initiatives Program of the Korean Ministry of Science and Technology (to EK); the Korea Science and Engineering Foundation M10500000049-05J0000-04900 (to HK); Telethon-Italy GGP06208, Fondazione Cariplo 2006-0779, and Compagnia di San Paolo 2005-1964 (to CS); and a National Institute of Health grant R01MH064801 (to TM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: AMPAR, AMPA receptor; CA1, CA1 pyramidal cell; EPSC, excitatory postsynaptic current; GVDN, G23VD49N; LFS, low-frequency electrical stimulation; LTD, long-term depression; mEPSCs, miniature EPSCs; mGluR, metabotropic glutamate receptor; NMDAR, NMDA receptor; PKA, protein kinase A; POB1 CC, CC domain of POB1; PP1, protein phosphatase 1; PP2A, protein phosphatase 2A; PPF, paired-pulse facilitation; PP-LFS, paired-pulse LFS; RalBD, Ral binding domain of RalBP1; SC, Schaffer collateral; shRNA, short hairpin RNA; TBS, theta-burst stimulation; WT, wild-type
# These authors contributed equally to this work.
¤ Current address: Department of Biological Sciences, Korea Advances Institute of Science and Technology (KAIST), Daejeon, Korea
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