Tomohisa Hosokawa

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Bibliography

  • 2005 Graduated from Department of Biological sciences, Tokyo Metropolitan University
  • 2010 Ph.D. Graduate School of Sciences, Tokyo Metropolitan University
  • 2010-2017 Post-doc, Lab. for Memory Mechanisms, Brain Science Institute, RIKEN.
  • 2017-2021 Post-doc, Lab. for systems neuropharmacology, Department of Pharmacology, Graduate school of medicine, Kyoto University.
  • 2021-2023 Lecturer, Lab. for Cell regulation, Graduate school of Sciences, Nagoya University.
  • 2023-present Specially Appointed Lecturer. Lab. for systems neuropharmacology, Department of Pharmacology, Graduate school of medicine, Kyoto University.

Research topics

Molecular mechanisms for synaptic plasticity and Memory formation

Synaptic plasticity, such as synaptic potentiation and depression, are known as the fundamental mechanisms of memory formation, but their molecular regulatory mechanisms are not yet fully understood. In my research, I have focused on post-translational modifications of synaptic proteins, particularly phosphorylation, and have examined their spatiotemporal regulation. Of particular interest is the activation of CaMKII, also known as the major postsynaptic protein. It responds to the influx of calcium ions during learning, undergoes conformational changes, and exhibits kinase activity. As its downstream, phosphorylation of the AMPA-type glutamate receptor (AMPA receptor) has been highlighted, but its significance has remained unclear. Therefore, using the Phos-tag method, a quantitative analysis technique that I have employed in previous studies, I evaluated the level of phosphorylation at synapses. The results showed that the phosphorylation level is extremely low, suggesting limited involvement in memory formation.

Segregation of AMPA receptor and NMDA receptor as liquid-phase nanodomains

While AMPA receptors are known as the main mediators of information transmission, the NMDA-type glutamate receptor (NMDA receptor) is involved in plasticity. In my research, I have discovered a mechanism that the activation of CaMKII leads to the formation of distinct nanodomains for these receptors, allowing them to segregate by mutually excluding each other. Furthermore, these nanodomains possess properties of a liquid phase, ensuring fluidity, reactivity, and reversibility. This finding is consistent with the bidirectional nature of synaptic plasticity. Other constituent factors are also present within these nanodomains, and particularly, I have found that Neuroligin participated in the nanodomain of the AMPA receptor, which has the potential to concentrate signals on the AMPA receptor side while attenuating signals on the NMDA receptor side. This discovery provides a possible explanation for the simultaneous enhancement of synaptic strength and reduction of plasticity.

postsynaptic liquid-phase nanodomains and their cross-talk

Based on this background, I am driving research to elucidate the principles and significance of liquid-phase nanodomain formation and to explore strategies for manipulating them. Here are the research approaches I am pursuing:

1. Identification of nanodomain constituent factors using TurboID and comprehensive identification of binding interfaces using Alphafold-multimer. By employing TurboID, I aim to identify the factors involved in nanodomain assembly. Additionally, I utilize Alphafold-multimer to comprehensively identify the binding interfaces within these nanodomains among all PSD proteins.

2. Visualization of glutamate levels received by nanodomains using glutamate sensors. To understand the dynamics of nanodomain function, I employ glutamate biosensors to visualize the amount of glutamate received by these nanodomains.

3. Factors that disrupt nanodomains and their impact on synaptic strength. I am investigating the factors that can disrupt the segregation of nanodomains and examining their effects on synaptic strength. By understanding these significance, we can gain new insights into the regulation of synaptic plasticity.

4. Optical manipulation of nanodomains. I am exploring methods to optically control the formation and dispersion of nanodomains, enabling precise modulation of their properties and functions.

Through these research endeavors, I aim to deepen our understanding of liquid-phase nanodomain formation, elucidate their functional significance, and open the way for potential manipulations and applications in the context of synaptic plasticity.


Publications

  1. Hosokawa, T., & Liu, P.W. (2021).
    Regulation of the Stability and Localization of Post-synaptic Membrane Proteins by Liquid-Liquid Phase Separation. Frontiers in physiology, 12, 795757. [PubMed:34975543] [PMC] [WorldCat] [DOI]
  2. Hosokawa, T., Liu, P.W., Cai, Q., Ferreira, J.S., Levet, F., Butler, C., Sibarita, J.B., Choquet, D., Groc, L., Hosy, E., Zhang, M., & Hayashi, Y. (2021).
    CaMKII activation persistently segregates postsynaptic proteins via liquid phase separation. Nature neuroscience, 24(6), 777-785. [PubMed:33927400] [WorldCat] [DOI]
  3. Liu, P.W., Hosokawa, T., & Hayashi, Y. (2021).
    Regulation of synaptic nanodomain by liquid-liquid phase separation: A novel mechanism of synaptic plasticity. Current opinion in neurobiology, 69, 84-92. [PubMed:33752045] [WorldCat] [DOI]
  4. Eriksen, M.S., Nikolaienko, O., Hallin, E.I., Grødem, S., Bustad, H.J., Flydal, M.I., Merski, I., Hosokawa, T., Lascu, D., Akerkar, S., Cuéllar, J., Chambers, J.J., O'Connell, R., Muruganandam, G., Loris, R., Touma, C., Kanhema, T., Hayashi, Y., Stratton, M.M., Valpuesta, J.M., Kursula, P., Martinez, A., & Bramham, C.R. (2021).
    Arc self-association and formation of virus-like capsids are mediated by an N-terminal helical coil motif. The FEBS journal, 288(9), 2930-2955. [PubMed:33175445] [WorldCat] [DOI]
  5. Cai, Q., Hosokawa, T., Zeng, M., Hayashi, Y., & Zhang, M. (2020).
    Shank3 Binds to and Stabilizes the Active Form of Rap1 and HRas GTPases via Its NTD-ANK Tandem with Distinct Mechanisms. Structure (London, England : 1993), 28(3), 290-300.e4. [PubMed:31879129] [WorldCat] [DOI]
  6. Hallin, E.I., Eriksen, M.S., Baryshnikov, S., Nikolaienko, O., Grødem, S., Hosokawa, T., Hayashi, Y., Bramham, C.R., & Kursula, P. (2018).
    Structure of monomeric full-length ARC sheds light on molecular flexibility, protein interactions, and functional modalities. Journal of neurochemistry, 147(3), 323-343. [PubMed:30028513] [WorldCat] [DOI]
  7. Kimura, T., Hosokawa, T., Taoka, M., Tsutsumi, K., Ando, K., Ishiguro, K., Hosokawa, M., Hasegawa, M., & Hisanaga, S. (2016).
    Quantitative and combinatory determination of in situ phosphorylation of tau and its FTDP-17 mutants. Scientific reports, 6, 33479. [PubMed:27641626] [PMC] [WorldCat] [DOI]
  8. Kim, K., Saneyoshi, T., Hosokawa, T., Okamoto, K., & Hayashi, Y. (2016).
    Interplay of enzymatic and structural functions of CaMKII in long-term potentiation. Journal of neurochemistry, 139(6), 959-972. [PubMed:27207106] [WorldCat] [DOI]
  9. Hosokawa, T., Mitsushima, D., Kaneko, R., & Hayashi, Y. (2015).
    Stoichiometry and phosphoisotypes of hippocampal AMPA-type glutamate receptor phosphorylation. Neuron, 85(1), 60-67. [PubMed:25533481] [PMC] [WorldCat] [DOI]
  10. Kobayashi, H., Saito, T., Sato, K., Furusawa, K., Hosokawa, T., Tsutsumi, K., Asada, A., Kamada, S., Ohshima, T., & Hisanaga, S. (2014).
    Phosphorylation of cyclin-dependent kinase 5 (Cdk5) at Tyr-15 is inhibited by Cdk5 activators and does not contribute to the activation of Cdk5. The Journal of biological chemistry, 289(28), 19627-36. [PubMed:24872417] [PMC] [WorldCat] [DOI]
  11. de Thonel, A., Ferraris, S.E., Pallari, H.M., Imanishi, S.Y., Kochin, V., Hosokawa, T., Hisanaga, S., Sahlgren, C., & Eriksson, J.E. (2010).
    Protein kinase Czeta regulates Cdk5/p25 signaling during myogenesis. Molecular biology of the cell, 21(8), 1423-34. [PubMed:20200223] [PMC] [WorldCat] [DOI]
  12. Hosokawa, T., Saito, T., Asada, A., Fukunaga, K., & Hisanaga, S. (2010).
    Quantitative measurement of in vivo phosphorylation states of Cdk5 activator p35 by Phos-tag SDS-PAGE. Molecular & cellular proteomics : MCP, 9(6), 1133-43. [PubMed:20097924] [PMC] [WorldCat] [DOI]
  13. Nguyen, C., Hosokawa, T., Kuroiwa, M., Ip, N.Y., Nishi, A., Hisanaga, S., & Bibb, J.A. (2007).
    Differential regulation of the Cdk5-dependent phosphorylation sites of inhibitor-1 and DARPP-32 by depolarization. Journal of neurochemistry, 103(4), 1582-93. [PubMed:17868322] [WorldCat] [DOI]
  14. Saito, T., Konno, T., Hosokawa, T., Asada, A., Ishiguro, K., & Hisanaga, S. (2007).
    p25/cyclin-dependent kinase 5 promotes the progression of cell death in nucleus of endoplasmic reticulum-stressed neurons. Journal of neurochemistry, 102(1), 133-40. [PubMed:17506859] [WorldCat] [DOI]
  15. Hosokawa, T., Saito, T., Asada, A., Ohshima, T., Itakura, M., Takahashi, M., Fukunaga, K., & Hisanaga, S. (2006).
    Enhanced activation of Ca2+/calmodulin-dependent protein kinase II upon downregulation of cyclin-dependent kinase 5-p35. Journal of neuroscience research, 84(4), 747-54. [PubMed:16802322] [WorldCat] [DOI]

Funding & Awards

  • Grant-in-Aid for start-up
  • Grant-in-Aid for Young Scientists (B)　
  • Grant-in-Aid for international research promotion (A)
  • Takeda foundation
  • Narishige foundation
  • Research-foundation for opto-science and technology
  • Inamori foundation
  • Kobayashi foundation

Teaching Experience

  • Class for basic biology
  • Class for basic biochemistry
  • Class for Journal reading
  • Class for research presentation
  • Experimental Class for heart
  • Experimental Class for the observation of human blood
  • Experimental Class for surgery and behavioral analysis of mouse

Academic Society

  • Society for Neuroscience (JP)
  • Society for Neurochemistry (JP)
  • Society for Biochemistry (JP)
  • The molecular biology society Japan (JP)

Personal Interests

Muscle training, Playing with my 2 yo-son

Contact Address

Department of Pharmacology
Kyoto University Graduate School of Medicine
Room 403, Building A
Kyoto 606-8501 Japan E-mail: hosokawa.tomohisa.5s@kyoto-u.ac.jp

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