Vanderbilt University School of Medicine

Nakagawa, Terunaga , M.D. Ph.D.
Associate Professor of Molecular Physiology and Biophysics

Lab Url: http://www.mc.vanderbilt.edu/root/vumc.php?site=terunaganakagawa

Phone Number: 615-875-2531

Email Address:terunaga.nakagawa@vanderbilt.edu

Nakagawa, Terunaga's picture

Office Address   Mailing Address

Robinson Research Building 766

702 Light Hall (0615) 37232-0615


Research Keywords
iGluR, glutamate receptors, synapse, postsynaptic density, AMPA receptor, NMDA receptor, kainate receptor, stargazin, TARP, GSG1L, cornichon, neurexin, GluA2, electron microscopy, cell biology, single particle analysis, image processing, non coding RNA, RNAi, X-ray crystallography, biochemistry, membrane biochemistry, protein purification, macromolecular assembly, ion channel, receptor trafficking, receptor modulation, ion channel modulation,Biochemistry,Membrane,Neuroscience,Pharmacology,Physiology,Protein Structure,Proteomics,Receptor,Structural Biology

Research Specialty
Molecular and cellular biophysics of synapses

Research Description
(1) The subunit assembly mechanism and architecture of the ionotropic glutamate receptors.

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channel that are critical for excitatory neurotransmission. They are divided into three subtypes (AMPA, NMDA and kainite receptors) based on their pharmacological characteristics. The heteroterameric AMPA receptors play pivotal roles in synaptic plasticity. Their dysfunction is related to a variety of psychiatric and neurological disorders, including schizophrenia, Alzheimera??s disease, ALS, X-linked mental retardation, limbic encephalitis, CNS lupus, and Rasmussena??s encephalitis.

The exact function and trafficking of these receptors depends critically on their subunit composition and organization. However, because of the limited structural information available on native full-length AMPA receptors, the molecular basis for the function, trafficking, and biogenesis of AMPA receptors remains poorly understood. We study the subunit assembly mechanism and the structures of fully assembled AMPA receptors as well as their assembly intermediates.

Our ultimate goal is to identify the structural basis for the function and modulation of AMPA receptors. By investigating recombinant AMPA receptors and genetic variants, we aim to extend our previous electron microscopy studies of brain-derived AMPA receptors. Our research further extends into understanding the molecular assembly and function of NMDA receptors. The precise knowledge of the molecular mechanism of ionotropic glutamate receptor function will pave the path toward developing new drugs for treating a variety of neurological and psychiatric disorders.

(2) AMPA and kainite receptor interactomes facilitate identifying novel functional repertoire of iGluRs

The iGluRs are protein complexes formed of tetrameric assembly of core receptor subunits and auxiliary transmembrane subunits. In the case of AMPA-Rs the auxiliary (and candidate auxiliary) subunits include, stargazin/TARPs, SOL-1, cornichon, CKAMP44/Shisa-9, and synDIG1. Each auxiliary subunit modulates channel trafficking and gating is specific ways. The functional variety of AMPA-Rs is therefore amplified by combinatorial effect caused by different types of AMPA-Rs binding to distinct auxiliary subunits.

The magnitude of molecular variety of iGluR auxiliary (or candidate auxiliary) subunit remains elusive. To gain insight into this question, we have recently conducted a comparative interactome analyses of AMPA and kainite receptors purified from rat brain (Shanks, Savas, Maruo et al. 2012, Cell Reports). With the aid of this large-scale data we were able to identify many candidate auxiliary subunits and/or potential binding partners of AMPA-R and kainite receptors. Among those candidates we have verified GSG1L as novel AMPA-R auxiliary subunit, based on experimental verification by combining methods in biochemistry, electrophysiology and cell biology. In-depth analyses of the biology revolving around GSG1L and further investigation of other potential iGluR interacting membrane proteins identified in our comparative interactome data may reveal novel physiological functions of AMPA-Rs.

(3) Isolation of novel macromolecular complexes from the neuronal membrane.

We believe that there are still novel macromolecules in the membrane that play fundamentally important biological function. Using our strength in membrane biochemistry, we develop new biochemical procedures to isolate new macromolecules from the neuronal membrane. Our interest is not only limited to prototypical transmembrane proteins but also to other molecular entities such as lipid clusters, glycolipid complex, and RNAs. This high-risk high-reward project is partly funded by the NIH EUREKA (Exceptional and Unconventional Research Enabling Knowledge Acceleration) Grant


Publications
Shanks, NF, Savas, JN, Maruo, T, Cais, O, Hirao, A, Oe, S, Ghosh, A, Noda, Y, Greger, IH, Yates, JR, Nakagawa, T. Differences in AMPA and kainate receptor interactomes facilitate identification of AMPA receptor auxiliary subunit GSG1L. Cell Rep, 1(6), 590-8, 2012. PMCID:3401968

Farina, AN, Blain, KY, Maruo, T, Kwiatkowski, W, Choe, S, Nakagawa, T. Separation of domain contacts is required for heterotetrameric assembly of functional NMDA receptors. J Neurosci, 31(10), 3565-79, 2011. PMCID:3063151

Nakagawa, T, Hoogenraad, CC. Lentiviral transgenesis. Methods Mol Biol, 693, 117-42, 2011.

Comoletti, D, Miller, MT, Jeffries, CM, Wilson, J, Demeler, B, Taylor, P, Trewhella, J, Nakagawa, T. The macromolecular architecture of extracellular domain of alphaNRXN1: domain organization, flexibility, and insights into trans-synaptic disposition. Structure, 18(8), 1044-53, 2010. PMCID:2948785

Nakagawa, T. The biochemistry, ultrastructure, and subunit assembly mechanism of AMPA receptors. Mol Neurobiol, 42(3), 161-84, 2010. PMCID:2992128

Shanks, NF, Maruo, T, Farina, AN, Ellisman, MH, Nakagawa, T. Contribution of the global subunit structure and stargazin on the maturation of AMPA receptors. J Neurosci, 30(7), 2728-40, 2010. PMCID:2842908

Fischer, A, Garcia-Rodriguez, C, Geren, I, Lou, J, Marks, JD, Nakagawa, T, Montal, M. Molecular architecture of botulinum neurotoxin E revealed by single particle electron microscopy. J Biol Chem, 283(7), 3997-4003, 2008.

Cheng, D, Hoogenraad, CC, Rush, J, Ramm, E, Schlager, MA, Duong, DM, Xu, P, Wijayawardana, SR, Hanfelt, J, Nakagawa, T, Sheng, M, Peng, J. Relative and absolute quantification of postsynaptic density proteome isolated from rat forebrain and cerebellum. Mol Cell Proteomics, 5(6), 1158-70, 2006.

Nakagawa, T, Cheng, Y, Sheng, M, Walz, T. Three-dimensional structure of an AMPA receptor without associated stargazin/TARP proteins. Biol Chem, 387(2), 179-87, 2006. PMCID:2842908

Nakagawa, T, Feliu-Mojer, MI, Wulf, P, Lois, C, Sheng, M, Hoogenraad, CC. Generation of lentiviral transgenic rats expressing glutamate receptor interacting protein 1 (GRIP1) in brain, spinal cord and testis. J Neurosci Methods, 152(1-2), 1-9, 2006. PMCID:2842908

Chen, X, Vinade, L, Leapman, RD, Petersen, JD, Nakagawa, T, Phillips, TM, Sheng, M, Reese, TS. Mass of the postsynaptic density and enumeration of three key molecules. Proc Natl Acad Sci U S A, 102(32), 11551-6, 2005. PMCID:1182136

Nakagawa, T, Cheng, Y, Ramm, E, Sheng, M, Walz, T. Structure and different conformational states of native AMPA receptor complexes. Nature, 433(7025), 545-9, 2005. PMCID:2842908

Takao, K, Okamoto, K, Nakagawa, T, Neve, RL, Nagai, T, Miyawaki, A, Hashikawa, T, Kobayashi, S, Hayashi, Y. Visualization of synaptic Ca2+ /calmodulin-dependent protein kinase II activity in living neurons. J Neurosci, 25(12), 3107-12, 2005. PMCID:2842908

Nakagawa, T, Engler, JA, Sheng, M. The dynamic turnover and functional roles of alpha-actinin in dendritic spines. Neuropharmacology, 47(5), 734-45, 2004.

Nakagawa, T, Futai, K, Lashuel, HA, Lo, I, Okamoto, K, Walz, T, Hayashi, Y, Sheng, M. Quaternary structure, protein dynamics, and synaptic function of SAP97 controlled by L27 domain interactions. Neuron, 44(3), 453-67, 2004. PMCID:2842908

Schulz, TW, Nakagawa, T, Licznerski, P, Pawlak, V, Kolleker, A, Rozov, A, Kim, J, Dittgen, T, K??hr, G, Sheng, M, Seeburg, PH, Osten, P. Actin/alpha-actinin-dependent transport of AMPA receptors in dendritic spines: role of the PDZ-LIM protein RIL. J Neurosci, 24(39), 8584-94, 2004. PMCID:2842908

Passafaro, M, Nakagawa, T, Sala, C, Sheng, M. Induction of dendritic spines by an extracellular domain of AMPA receptor subunit GluR2. Nature, 424(6949), 677-81, 2003. PMCID:2842908

Nakajima, K, Takei, Y, Tanaka, Y, Nakagawa, T, Nakata, T, Noda, Y, Setou, M, Hirokawa, N. Molecular motor KIF1C is not essential for mouse survival and motor-dependent retrograde Golgi apparatus-to-endoplasmic reticulum transport. Mol Cell Biol, 22(3), 866-73, 2002. PMCID:133549

Sheng, M, Nakagawa, T. Neurobiology: glutamate receptors on the move. Nature, 417(6889), 601-2, 2002. PMCID:2842908

Zhao, C, Takita, J, Tanaka, Y, Setou, M, Nakagawa, T, Takeda, S, Yang, HW, Terada, S, Nakata, T, Takei, Y, Saito, M, Tsuji, S, Hayashi, Y, Hirokawa, N. Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta. Cell, 105(5), 587-97, 2001. PMCID:133549

Nakagawa, T, Setou, M, Seog, D, Ogasawara, K, Dohmae, N, Takio, K, Hirokawa, N. A novel motor, KIF13A, transports mannose-6-phosphate receptor to plasma membrane through direct interaction with AP-1 complex. Cell, 103(4), 569-81, 2000. PMCID:133549

Nakagawa, T, Sheng, M. Neurobiology. A stargazer foretells the way to the synapse. Science, 290(5500), 2270-1, 2000. PMCID:2842908

Setou, M, Nakagawa, T, Seog, DH, Hirokawa, N. Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport. Science, 288(5472), 1796-802, 2000. PMCID:133549

Nakagawa, T, Tanaka, Y, Matsuoka, E, Kondo, S, Okada, Y, Noda, Y, Kanai, Y, Hirokawa, N. Identification and classification of 16 new kinesin superfamily (KIF) proteins in mouse genome. Proc Natl Acad Sci U S A, 94(18), 9654-9, 1997. PMCID:23244

Nakagawa, T, Chen, J, Zhang, Z, Kanai, Y, Hirokawa, N. Two distinct functions of the carboxyl-terminal tail domain of NF-M upon neurofilament assembly: cross-bridge formation and longitudinal elongation of filaments. J Cell Biol, 129(2), 411-29, 1995. PMCID:2199923


Postdoctoral Position Available
Yes

Postdoctoral Position Details
Postdoctoral positions are available. Detail information can be found at the following URL: http://www.mc.vanderbilt.edu/root/vumc.php?site=terunaganakagawa

Updated Date
10/18/2012



Vanderbilt University is committed to principles of equal opportunity and affirmative action.
Copyright 2012 Vanderbilt University School of Medicine
The office of Biomedical Research Education & Training All rights reserved.
For questions or problems concerning this page, please submit a help ticket.