Terunaga Nakagawa
Last active: 4/10/2019

Profile

(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, Alzheimer’s disease, ALS, X-linked mental retardation, limbic encephalitis, CNS lupus, and Rasmussen’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

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. Structure-function analyses of the ion channel TRPC3 reveal that its cytoplasmic domain allosterically modulates channel gating. Sierra-Valdez F, Azumaya CM, Romero LO, Nakagawa T, Cordero-Morales JF (2018) J Biol Chem 293(41): 16102-16114
    › Primary publication · 30139744 (PubMed) · PMC6187627 (PubMed Central)
  2. Cryo-EM structure of the cytoplasmic domain of murine transient receptor potential cation channel subfamily C member 6 (TRPC6). Azumaya CM, Sierra-Valdez F, Cordero-Morales JF, Nakagawa T (2018) J Biol Chem 293(26): 10381-10391
    › Primary publication · 29752403 (PubMed) · PMC6028952 (PubMed Central)
  3. Amyloid Accumulation Drives Proteome-wide Alterations in Mouse Models of Alzheimer's Disease-like Pathology. Savas JN, Wang YZ, DeNardo LA, Martinez-Bartolome S, McClatchy DB, Hark TJ, Shanks NF, Cozzolino KA, Lavallée-Adam M, Smukowski SN, Park SK, Kelly JW, Koo EH, Nakagawa T, Masliah E, Ghosh A, Yates JR (2017) Cell Rep 21(9): 2614-2627
    › Primary publication · 29186695 (PubMed) · PMC5726791 (PubMed Central)
  4. A novel mechanism for Ca/calmodulin-dependent protein kinase II targeting to L-type Ca channels that initiates long-range signaling to the nucleus. Wang X, Marks CR, Perfitt TL, Nakagawa T, Lee A, Jacobson DA, Colbran RJ (2017) J Biol Chem 292(42): 17324-17336
    › Primary publication · 28916724 (PubMed) · PMC5655510 (PubMed Central)
  5. Engineering defined membrane-embedded elements of AMPA receptor induces opposing gating modulation by cornichon 3 and stargazin. Hawken NM, Zaika EI, Nakagawa T (2017) J Physiol 595(20): 6517-6539
    › Primary publication · 28815591 (PubMed) · PMC5638889 (PubMed Central)
  6. Screening for AMPA receptor auxiliary subunit specific modulators. Azumaya CM, Days EL, Vinson PN, Stauffer S, Sulikowski G, Weaver CD, Nakagawa T (2017) PLoS One 12(3): e0174742
    › Primary publication · 28358902 (PubMed) · PMC5373622 (PubMed Central)
  7. A Novel Human Mutation Disrupts Dendritic Morphology and Synaptic Transmission, and Causes ASD-Related Behaviors. Stephenson JR, Wang X, Perfitt TL, Parrish WP, Shonesy BC, Marks CR, Mortlock DP, Nakagawa T, Sutcliffe JS, Colbran RJ (2017) J Neurosci 37(8): 2216-2233
    › Primary publication · 28130356 (PubMed) · PMC5338762 (PubMed Central)
  8. Structural basis for integration of GluD receptors within synaptic organizer complexes. Elegheert J, Kakegawa W, Clay JE, Shanks NF, Behiels E, Matsuda K, Kohda K, Miura E, Rossmann M, Mitakidis N, Motohashi J, Chang VT, Siebold C, Greger IH, Nakagawa T, Yuzaki M, Aricescu AR (2016) Science 353(6296): 295-9
    › Primary publication · 27418511 (PubMed) · PMC5291321 (PubMed Central)
  9. Structural basis for extracellular cis and trans RPTPσ signal competition in synaptogenesis. Coles CH, Mitakidis N, Zhang P, Elegheert J, Lu W, Stoker AW, Nakagawa T, Craig AM, Jones EY, Aricescu AR (2014) Nat Commun : 5209
    › Primary publication · 25385546 (PubMed) · PMC4239663 (PubMed Central)
  10. Molecular dissection of the interaction between the AMPA receptor and cornichon homolog-3. Shanks NF, Cais O, Maruo T, Savas JN, Zaika EI, Azumaya CM, Yates JR, Greger I, Nakagawa T (2014) J Neurosci 34(36): 12104-20
    › Primary publication · 25186755 (PubMed) · PMC4152608 (PubMed Central)
  11. Differences in AMPA and kainate receptor interactomes facilitate identification of AMPA receptor auxiliary subunit GSG1L. Shanks NF, Savas JN, Maruo T, Cais O, Hirao A, Oe S, Ghosh A, Noda Y, Greger IH, Yates JR, Nakagawa T (2012) Cell Rep 1(6): 590-8
    › Primary publication · 22813734 (PubMed) · PMC3401968 (PubMed Central)