Updated on 2024/10/17

写真a

 
TAKEMOTO-KIMURA Sayaka MD PhD
 
Organization
Research Institute of Environmental Medicine Division of Stress Recognition and Response Professor
Graduate School
Graduate School of Medicine
Title
Professor
Contact information
メールアドレス

Degree 1

  1. 博士（医学） （ 2003.9   京都大学 ） 

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Research Areas 2

  1. Others / Others  / 分子神経科学

  2. Others / Others  / Molecular Neuroscience

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Research History 4

  1. Professor, Research institute of Environmental Medicine, Nagoya University

    2015.7

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    Country：Japan

  2. Assistant Professor, Department of Neurochemistry, The University of Tokyo Graduate School of Medicine

    2014.4 - 2015.6

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    Country：Japan

  3. Junior Assistant Professor, Department of Neurochemistry, The University of Tokyo Graduate School of Medicine

    2003.10 - 2014.3

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    Country：Japan

  4. Resident, Nagoya University Hospital

    1999.6 - 2000.3

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    Country：Japan

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Education 2

  1. Kyoto University   Graduate School, Division of Medicine

    - 2003

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    Country： Japan

  2. Nagoya University   Faculty of Medicine

    - 1999

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    Country： Japan

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Awards 1

  1. 日本神経化学会奨励賞

    2012   日本神経化学会  

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    Country：Japan

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Papers 36

  1. [Exploring the molecular and neuronal bases involved in central amygdala-dependent control of emotional behaviors].

    Shuhei Ueda, Sayaka Takemoto-Kimura

    Nihon yakurigaku zasshi. Folia pharmacologica Japonica   Vol. 159 ( 5 ) page： 316 - 320   2024

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    Language：Japanese   Publishing type：Research paper (scientific journal)  

    The central extended amygdala, including the central nucleus of the amygdala (CeA) and the lateral division of the bed nucleus of the stria terminalis (BNSTL), is a pivotal brain region involved in the threat processing responsible for emotional states such as fear and anxiety. These brain regions alter their circuit activities and exhibit necessary functions to adapt to environmental changes. When faced with excessive threats or stress, it is thought that these neural circuit functions are disrupted and cause various stress-related psychiatric disorders. The CeA and BNSTL were suggested to be the same nuclei separated during development because of their dense neural connections, and the similarities in cellular composition and connectivity patterns with other brain regions. On the other side, some recent studies suggested functional differences between these two regions in controlling emotional behaviors. However, functional segregation at the subnuclei level was insufficient since the two regions have complex circuit structures composed of multiple subnuclei. In this review, we introduce the similarities and differences between the CeA and BNSTL that have been clarified from our recent comparative studies of gene expression profiles and circuit functions at the subnuclei level. Additionally, we also discuss how it can contribute to understanding the molecular pathogenesis of neuropsychiatric disorders, including stress-related psychiatric disorders.

    DOI： 10.1254/fpj.23052

    PubMed

  2. Lipidation states orchestrate CLICK-III/CaMKIγ's stepwise association with Golgi and rafts-enriched membranes and specify its functional coupling to STEF-Rac1-dependent neurite extension Reviewed

    Natsumi Ageta-Ishihara, Sayaka Takemoto-Kimura, Yayoi Kondo, Michiko Okamura, Haruhiko Bito

    Frontiers in Cellular Neuroscience   Vol. 17   2023.8

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    Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

    CLICK-III/CaMKIγ is a lipid-anchored neuronal isoform of multifunctional Ca<sup>2+</sup>/calmodulin-dependent protein kinases, which mediates BDNF-dependent dendritogenesis in cultured cortical neurons. We found that two distinct lipidation states of CaMKIγ, namely, prenylation and palmitoylation, controlled its association with detergent-resistant microdomains in the dendrites and were essential for its dendritogenic activity. However, the impact of each lipid modification on membrane targeting/trafficking and how it specifies functional coupling leading to polarized changes in neuronal morphology are not clear. Here, we show that prenylation induces membrane anchoring of CaMKIγ, permitting access to the Golgi apparatus, and a subsequent palmitoylation facilitates association with cholesterol-enriched lipid microdomains or lipid rafts, in particular at the Golgi. To specifically test the role of palmitoylated CaMKγ in neurite extension, we identified and took advantage of a cell system, PC12, which, unlike neurons, conveniently lacked CaMKIγ and was deficient in the activity-dependent release of a neuritogenic growth factor while possessing the ability to activate polarized rafts signaling for morphogenesis. This system allowed us to rigorously demonstrate that an activity-dependent, lipid rafts-restricted Rac activation leading to neuritogenesis could be functionally rescued by dually lipidated CaMKIγ expression, revealing that not only prenylation but also palmitoylation is essential for CaMKIγ to activate a compartmentalized STEF-Rac1 pathway. These results shed light on the significance of recruiting prenylated and palmitoylated CaMKIγ into the coalescing signalosomes at lipid rafts together with Rac1 and its specific GEF and STEF and forming a compartmentalized Ca<sup>2+</sup> signaling pathway that underlies activity-dependent neuritogenesis and morphogenesis during axodendritic polarization critical for brain development and circuitogenesis.

    DOI： 10.3389/fncel.2023.1204302

    Web of Science

    PubMed

  3. Experience-dependent changes in affective valence of taste in male mice. Reviewed International journal

    Shun Hamada, Kaori Mikami, Shuhei Ueda, Masashi Nagase, Takashi Nagashima, Mikiyasu Yamamoto, Haruhiko Bito, Sayaka Takemoto-Kimura, Toshihisa Ohtsuka, Ayako M Watabe

    Molecular brain   Vol. 16 ( 1 ) page： 28 - 28   2023.3

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    Language：English   Publishing type：Research paper (scientific journal)  

    Taste plays an essential role in the evaluation of food quality by detecting potential harm and benefit in what animals are about to eat and drink. While the affective valence of taste signals is supposed to be innately determined, taste preference can also be drastically modified by previous taste experiences of the animals. However, how the experience-dependent taste preference is developed and the neuronal mechanisms involved in this process are poorly understood. Here, we investigate the effects of prolonged exposure to umami and bitter tastants on taste preference using two-bottle tests in male mice. Prolonged umami exposure significantly enhanced umami preference with no changes in bitter preference, while prolonged bitter exposure significantly decreased bitter avoidance with no changes in umami preference. Because the central amygdala (CeA) is postulated as a critical node for the valence processing of sensory information including taste, we examined the responses of cells in the CeA to sweet, umami, and bitter tastants using in vivo calcium imaging. Interestingly, both protein kinase C delta (Prkcd)-positive and Somatostatin (Sst)-positive neurons in the CeA showed an umami response comparable to the bitter response, and no difference in cell type-specific activity patterns to different tastants was observed. Meanwhile, fluorescence in situ hybridization with c-Fos antisense probe revealed that a single umami experience significantly activates the CeA and several other gustatory-related nuclei, and especially CeA Sst-positive neurons were strongly activated. Intriguingly, after prolonged umami experience, umami tastant also significantly activates the CeA neurons, but the Prkcd-positive neurons instead of Sst-positive neurons were highly activated. These results suggest a relationship between amygdala activity and experience-dependent plasticity developed in taste preference and the involvement of the genetically defined neural populations in this process.

    DOI： 10.1186/s13041-023-01017-x

    PubMed

  4. Förster resonance energy transfer-based kinase mutation phenotyping reveals an aberrant facilitation of Ca2+/calmodulin-dependent CaMKIIα activity in de novo mutations related to intellectual disability. International journal

    Hajime Fujii, Hiroyuki Kidokoro, Yayoi Kondo, Masahiro Kawaguchi, Shin-Ichiro Horigane, Jun Natsume, Sayaka Takemoto-Kimura, Haruhiko Bito

    Frontiers in molecular neuroscience   Vol. 15   page： 970031 - 970031   2022.9

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    Language：English   Publishing type：Research paper (scientific journal)  

    CaMKIIα plays a fundamental role in learning and memory and is a key determinant of synaptic plasticity. Its kinase activity is regulated by the binding of Ca2+/CaM and by autophosphorylation that operates in an activity-dependent manner. Though many mutations in CAMK2A were linked to a variety of neurological disorders, the multiplicity of its functional substrates renders the systematic molecular phenotyping challenging. In this study, we report a new case of CAMK2A P212L, a recurrent mutation, in a patient with an intellectual disability. To quantify the effect of this mutation, we developed a FRET-based kinase phenotyping strategy and measured aberrance in Ca2+/CaM-dependent activation dynamics in vitro and in synaptically connected neurons. CaMKIIα P212L revealed a significantly facilitated Ca2+/CaM-dependent activation in vitro. Consistently, this mutant showed faster activation and more delayed inactivation in neurons. More prolonged kinase activation was also accompanied by a leftward shift in the CaMKIIα input frequency tuning curve. In keeping with this, molecular phenotyping of other reported CAMK2A de novo mutations linked to intellectual disability revealed aberrant facilitation of Ca2+/CaM-dependent activation of CaMKIIα in most cases. Finally, the pharmacological reversal of CAMK2A P212L phenotype in neurons was demonstrated using an FDA-approved NMDA receptor antagonist memantine, providing a basis for targeted therapeutics in CAMK2A-linked intellectual disability. Taken together, FRET-based kinase mutation phenotyping sheds light on the biological impact of CAMK2A mutations and provides a selective, sensitive, quantitative, and scalable strategy for gaining novel insights into the molecular etiology of intellectual disability.

    DOI： 10.3389/fnmol.2022.970031

    Web of Science

    PubMed

  5. A Flp-dependent G-CaMP9a transgenic mouse for neuronal imaging in vivo

    Masayuki Sakamoto, Masatoshi Inoue, Atsuya Takeuchi, Shigetaka Kobari, Tatsushi Yokoyama, Shin-ichiro Horigane, Sayaka Takemoto-Kimura, Manabu Abe, Kenji Sakimura, Masanobu Kano, Kazuo Kitamura, Hajime Fujii, Haruhiko Bito

    Cell Reports Methods   Vol. 2 ( 2 ) page： 100168 - 100168   2022.2

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

    DOI： 10.1016/j.crmeth.2022.100168

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    PubMed

  6. Identification of ultra-rare disruptive variants in voltage-gated calcium channel-encoding genes in Japanese samples of schizophrenia and autism spectrum disorder

    Wang Chenyao, Horigane Shin-ichiro, Wakamori Minoru, Ueda Shuhei, Kawabata Takeshi, Fujii Hajime, Kushima Itaru, Kimura Hiroki, Ishizuka Kanako, Nakamura Yukako, Iwayama Yoshimi, Ikeda Masashi, Iwata Nakao, Okada Takashi, Aleksic Branko, Mori Daisuke, Yoshida Takashi, Bito Haruhiko, Yoshikawa Takeo, Takemoto-Kimura Sayaka, Ozaki Norio

    TRANSLATIONAL PSYCHIATRY   Vol. 12 ( 1 )   2022.2

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    Language：Japanese   Publishing type：Research paper (scientific journal)  

    DOI： 10.1038/s41398-022-01851-y

    Web of Science

  7. Distinctive Regulation of Emotional Behaviors and Fear-Related Gene Expression Responses in Two Extended Amygdala Subnuclei With Similar Molecular Profiles

    Ueda Shuhei, Hosokawa Masahito, Arikawa Koji, Takahashi Kiyofumi, Fujiwara Mao, Kakita Manami, Fukada Taro, Koyama Hiroaki, Horigane Shin-ichiro, Itoi Keiichi, Kakeyama Masaki, Matsunaga Hiroko, Takeyama Haruko, Bito Haruhiko, Takemoto-Kimura Sayaka

    FRONTIERS IN MOLECULAR NEUROSCIENCE   Vol. 14   2021.9

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    Language：Japanese   Publishing type：Research paper (scientific journal)  

    DOI： 10.3389/fnmol.2021.741895

    Web of Science

  8. Development of an L-type Ca2+ channel-dependent Ca2+ transient during the radial migration of cortical excitatory neurons. International journal

    Shin-Ichiro Horigane, Shun Hamada, Satoshi Kamijo, Hirokazu Yamada, Miwako Yamasaki, Masahiko Watanabe, Haruhiko Bito, Toshihisa Ohtsuka, Sayaka Takemoto-Kimura

    Neuroscience research   Vol. 169   page： 17 - 26   2021.8

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    Language：English   Publishing type：Research paper (scientific journal)  

    Increasing evidence has shown that voltage-gated L-type Ca2+ channels (LTCCs) are crucial for neurodevelopmental events, including neuronal differentiation/migration and neurite morphogenesis/extension. However, the time course of their functional maturation during the development of excitatory neurons remains unknown. Using a combination of fluorescence in situ hybridization and in utero electroporation-based labeling, we found that the transcripts of Cacna1c and Cacna1d, which encode the LTCC pore-forming subunits, were upregulated in the intermediate zone (IZ) during radial migration. Ca2+ imaging using GCaMP6s in acute brain slices showed spontaneous Ca2+ transients in migrating neurons throughout the IZ. Neurons in the IZ upper layer, especially in the multipolar-to-bipolar transition layer (TL), exhibited more frequent Ca2+ transients than adjacent layers and responded to FPL64176, a potent activator of LTCC. Consistently, nimodipine, an LTCC blocker, inhibited spontaneous Ca2+ transients in neurons in the TL. Collectively, we showed a hitherto unknown increased prevalence of LTCC-dependent Ca2+ transients in the TL of the IZ upper layer during the radial migration of excitatory neurons, which could be essential for the regulation of Ca2+-dependent neurodevelopmental processes.

    DOI： 10.1016/j.neures.2020.06.003

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    PubMed

  9. Remote control of neural function by X-ray-induced scintillation

    Matsubara Takanori, Yanagida Takayuki, Kawaguchi Noriaki, Nakano Takashi, Yoshimoto Junichiro, Sezaki Maiko, Takizawa Hitoshi, Tsunoda Satoshi P., Horigane Shin-ichiro, Ueda Shuhei, Takemoto-Kimura Sayaka, Kandori Hideki, Yamanaka Akihiro, Yamashita Takayuki

    NATURE COMMUNICATIONS   Vol. 12 ( 1 )   2021.7

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    Language：Japanese   Publishing type：Research paper (scientific journal)  

    DOI： 10.1038/s41467-021-24717-1

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  10. A mouse model of Timothy syndrome exhibits altered social competitive dominance and inhibitory neuron development

    Horigane Shin-ichiro, Ozawa Yukihiro, Zhang Jun, Todoroki Hiroe, Miao Pan, Haijima Asahi, Yanagawa Yuchio, Ueda Shuhei, Nakamura Shigeo, Kakeyama Masaki, Takemoto-Kimura Sayaka

    FEBS OPEN BIO   Vol. 10 ( 8 ) page： 1436 - 1446   2020.8

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    Publishing type：Research paper (scientific journal)  

    DOI： 10.1002/2211-5463.12924

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  11. Rational Engineering of XCaMPs, a Multicolor GECI Suite for In Vivo Imaging of Complex Brain Circuit Dynamics. Reviewed

    Inoue M, Takeuchi A, Manita S, Horigane SI, Sakamoto M, Kawakami R, Yamaguchi K, Otomo K, Yokoyama H, Kim R, Yokoyama T, Takemoto-Kimura S, Abe M, Okamura M, Kondo Y, Quirin S, Ramakrishnan C, Imamura T, Sakimura K, Nemoto T, Kano M, Fujii H, Deisseroth K, Kitamura K, Bito H

    Cell   Vol. 177 ( 5 ) page： 1346 - +   2019.5

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.cell.2019.04.007

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    PubMed

  12. Calcium signalling: a key regulator of neuronal migration

    Horigane Shin-ichiro, Ozawa Yukihiro, Yamada Hirokazu, Takemoto-Kimura Sayaka

    JOURNAL OF BIOCHEMISTRY   Vol. 165 ( 5 ) page： 401 - 409   2019.5

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    Publishing type：Research paper (scientific journal)  

    DOI： 10.1093/jb/mvz012

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  13. Retained Plasticity and Substantial Recovery of Rod-Mediated Visual Acuity at the Visual Cortex in Blind Adult Mice with Retinal Dystrophy

    Nishiguchi Koji M, Fujita Kosuke, Tokashiki Naoyuki, Komamura Hiroshi, Takemoto-Kimura Sayaka, Okuno Hiroyuki, Bito Haruhiko, Nakazawa Toru

    MOLECULAR THERAPY   Vol. 26 ( 10 ) page： 2397 - 2406   2018.10

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.ymthe.2018.07.012

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  14. A Critical Neurodevelopmental Role for L-Type Voltage-Gated Calcium Channels in Neurite Extension and Radial Migration. International journal

    Satoshi Kamijo, Yuichiro Ishii, Shin-Ichiro Horigane, Kanzo Suzuki, Masamichi Ohkura, Junichi Nakai, Hajime Fujii, Sayaka Takemoto-Kimura, Haruhiko Bito

    The Journal of neuroscience : the official journal of the Society for Neuroscience   Vol. 38 ( 24 ) page： 5551 - 5566   2018.6

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    Language：English   Publishing type：Research paper (scientific journal)  

    Despite many association studies linking gene polymorphisms and mutations of L-type voltage-gated Ca2+ channels (VGCCs) in neurodevelopmental disorders such as autism and schizophrenia, the roles of specific L-type VGCC during brain development remain unclear. Calcium signaling has been shown to be essential for neurodevelopmental processes such as sculpting of neurites, functional wiring, and fine tuning of growing networks. To investigate this relationship, we performed submembraneous calcium imaging using a membrane-tethered genetically encoded calcium indicator (GECI) Lck-G-CaMP7. We successfully recorded spontaneous regenerative calcium transients (SRCaTs) in developing mouse excitatory cortical neurons prepared from both sexes before synapse formation. SRCaTs originated locally in immature neurites independently of somatic calcium rises and were significantly more elevated in the axons than in dendrites. SRCaTs were not blocked by tetrodoxin, a Na+ channel blocker, but were strongly inhibited by hyperpolarization, suggesting a voltage-dependent source. Pharmacological and genetic manipulations revealed the critical importance of the Cav1.2 (CACNA1C) pore-forming subunit of L-type VGCCs, which were indeed expressed in immature mouse brains. Consistently, knocking out Cav1.2 resulted in significant alterations of neurite outgrowth. Furthermore, expression of a gain-of-function Cav1.2 mutant found in Timothy syndrome, an autosomal dominant multisystem disorder exhibiting syndromic autism, resulted in impaired radial migration of layer 2/3 excitatory neurons, whereas postnatal abrogation of Cav1.2 enhancement could rescue cortical malformation. Together, these lines of evidence suggest a critical role for spontaneous opening of L-type VGCCs in neural development and corticogenesis and indicate that L-type VGCCs might constitute a perinatal therapeutic target for neuropsychiatric calciochannelopathies.SIGNIFICANCE STATEMENT Despite many association studies linking gene polymorphisms and mutations of L-type voltage-gated Ca2+ channels (VGCCs) in neurodevelopmental disorders such as autism and schizophrenia, the roles of specific L-type VGCCs during brain development remain unclear. We here combined the latest Ca2+ indicator technology, quantitative pharmacology, and in utero electroporation and found a hitherto unsuspected role for L-type VGCCs in determining the Ca2+ signaling landscape of mouse immature neurons. We found that malfunctional L-type VGCCs in immature neurons before birth might cause errors in neuritic growth and cortical migration. Interestingly, the retarded corticogenesis phenotype was rescued by postnatal correction of L-type VGCC signal aberration. These findings suggest that L-type VGCCs might constitute a perinatal therapeutic target for neurodevelopment-associated psychiatric disorders.

    DOI： 10.1523/JNEUROSCI.2357-17.2018

    Web of Science

    PubMed

  15. Calmodulin kinases: essential regulators in health and disease Reviewed

    Sayaka Takemoto-Kimura, Kanzo Suzuki, Shin-Ichiro Horigane, Satoshi Kamijo, Masatoshi Inoue, Masayuki Sakamoto, Hajime Fujii, Haruhiko Bito

    JOURNAL OF NEUROCHEMISTRY   Vol. 141 ( 6 ) page： 808 - 818   2017.6

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    Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

    Neuronal activity induces intracellular Ca2+ increase, which triggers activation of a series of Ca2+-dependent signaling cascades. Among these, the multifunctional Ca2+/calmodulin-dependent protein kinases (CaMKs, or calmodulin kinases) play key roles in neuronal transmission, synaptic plasticity, circuit development and cognition. The most investigated CaMKs for these roles in neuronal functions are CaMKI, CaMKII, CaMKIV andwe will shed light on these neuronal CaMKs' functions in this review. Catalytically active members of CaMKs currently are CaMKI, CaMKII, CaMKIV and CaMKK. Although they all necessitate the binding of Ca2+ and calmodulin complex (Ca2+/CaM) for releasing autoinhibition, each member of CaMK has distinct activation mechanisms-autophosphorylation mediated autonomy of multimeric CaMKII and CaMKK-dependent phosphoswitch-induced activation of CaMKI or CaMKIV. Furthermore, each CaMK shows distinct subcellular localization that underlies specific compartmentalized function in each activated neuron. In this review, we first summarize these molecular characteristics of each CaMK as to regulation and subcellular localization, and then describe each biological function. In the last section, we also focus on the emerging role of CaMKs in pathophysiological conditions by introducing the recent studies, especially focusing on drug addiction and depression, and discuss how dysfunctional CaMKs may contribute to the pathology of the neuropsychological disorders.

    DOI： 10.1111/jnc.14020

    Web of Science

  16. Exploring the function of calcium-dependent phosphorylation in neuronal morphogenesis and circuit formation. Invited

    Takemoto-Kimura S and Horigane S

    Jpn. J. Neuropsychopharmaol.     page： 163-167   2017

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    Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 163-167

  17. Facilitation of axon outgrowth via a Wnt5a-CaMKK-CaMKIα pathway during neuronal polarization

    Horigane S*, Ageta-Ishihara N*, Kamijo S, Fujii H, Okamura M, Kinoshita M, Takemoto-Kimura S**, Bito H** (*co-first; **co-corresponding authors)

        2016.1

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1186/s13041-016-0189-3

  18. Rational design of a high-affinity, fast, red calcium indicator R-CaMP2.

    Inoue M, Takeuchi A, Horigane S, Ohkura M, Gengyo-Ando K, Fujii H, Kamijo S, Takemoto-Kimura S, Kano M, Nakai J, Kitamura K, Bito H

    Nature methods   Vol. 12 ( 1 ) page： 64-70   2015.1

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1038/nmeth.3185

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  19. Towards a better understanding of cognitive behaviors regulated by gene expression downstream of activity-dependent transcription factors.

    Nonaka M, Kim R, Sharry S, Matsushima A, Takemoto-Kimura S, Bito H

    Neurobiology of learning and memory   Vol. 115   page： 21-9   2014.11

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.nlm.2014.08.010

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  20. Region-specific activation of CRTC1-CREB signaling mediates long-term fear memory.

    Nonaka M, Kim R, Fukushima H, Sasaki K, Suzuki K, Okamura M, Ishii Y, Kawashima T, Kamijo S, Takemoto-Kimura S, Okuno H, Kida S, Bito H

    Neuron   Vol. 84 ( 1 ) page： 92-106   2014.10

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.neuron.2014.08.049

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  21. Functional labeling of neurons and their projections using the synthetic activity-dependent promoter E-SARE.

    Kawashima T, Kitamura K, Suzuki K, Nonaka M, Kamijo S, Takemoto-Kimura S, Kano M, Okuno H, Ohki K, Bito H

    Nature methods   Vol. 10 ( 9 ) page： 889-95   2013.9

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1038/nmeth.2559

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  22. Nonlinear decoding and asymmetric representation of neuronal input information by CaMKIIα and calcineurin.

      Vol. 3 ( 4 ) page： 978-87   2013.4

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.celrep.2013.03.033

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  23. Inverse synaptic tagging of inactive synapses via dynamic interaction of Arc/Arg3.1 with CaMKIIβ.

      Vol. 149 ( 4 ) page： 886-98   2012.5

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.cell.2012.02.062

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  24. Differential roles for CaM kinases in mediating excitation-morphogenesis coupling during formation and maturation of neuronal circuits.

    Takemoto-Kimura S, Suzuki K, Kamijo S, Ageta-Ishihara N, Fujii H, Okuno H, Bito H

    The European journal of neuroscience   Vol. 32 ( 2 ) page： 224-30   2010.7

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1111/j.1460-9568.2010.07353.x

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  25. Control of cortical axon elongation by a GABA-driven Ca2+/calmodulin-dependent protein kinase cascade.

    Ageta-Ishihara N, Takemoto-Kimura S, Nonaka M, Adachi-Morishima A, Suzuki K, Kamijo S, Fujii H, Mano T, Blaeser F, Chatila TA, Mizuno H, Hirano T, Tagawa Y, Okuno H, Bito H

    The Journal of neuroscience : the official journal of the Society for Neuroscience   Vol. 29 ( 43 ) page： 13720-9   2009.10

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1523/JNEUROSCI.3018-09.2009

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  26. Synaptic activity-responsive element in the Arc/Arg3.1 promoter essential for synapse-to-nucleus signaling in activated neurons.

    Kawashima T, Okuno H, Nonaka M, Adachi-Morishima A, Kyo N, Okamura M, Takemoto-Kimura S, Worley PF, Bito H

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 106 ( 1 ) page： 316-21   2009.1

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1073/pnas.0806518106

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  27. [Molecular mechanisms underlying the regulation of synapse function and the molecular architecture of the postsynaptic density].

    Bito H, Nonaka M, Fuse T, Fujii H, Takemoto-Kimura S, Okuno H

    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme   Vol. 53 ( 4 Suppl ) page： 418-23   2008.3

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    Language：Japanese   Publishing type：Research paper (scientific journal)  

    PubMed

  28. Regulation of dendritogenesis via a lipid-raft-associated Ca2+/calmodulin-dependent protein kinase CLICK-III/CaMKIgamma.

    Takemoto-Kimura S, Ageta-Ishihara N, Nonaka M, Adachi-Morishima A, Mano T, Okamura M, Fujii H, Fuse T, Hoshino M, Suzuki S, Kojima M, Mishina M, Okuno H, Bito H

    Neuron   Vol. 54 ( 5 ) page： 755-70   2007.6

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1016/j.neuron.2007.05.021

    PubMed

  29. Regulation of osteoclast differentiation and function by the CaMK-CREB pathway.

    Sato K, Suematsu A, Nakashima T, Takemoto-Kimura S, Aoki K, Morishita Y, Asahara H, Ohya K, Yamaguchi A, Takai T, Kodama T, Chatila TA, Bito H, Takayanagi H

    Nature medicine   Vol. 12 ( 12 ) page： 1410-6   2006.12

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1038/nm1515

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  30. Molecular identification and characterization of a family of kinases with homology to Ca2+/calmodulin-dependent protein kinases I/IV.

    Ohmae S, Takemoto-Kimura S, Okamura M, Adachi-Morishima A, Nonaka M, Fuse T, Kida S, Tanji M, Furuyashiki T, Arakawa Y, Narumiya S, Okuno H, Bito H

    The Journal of biological chemistry   Vol. 281 ( 29 ) page： 20427-39   2006.7

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1074/jbc.M513212200

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  31. Essential contribution of the ligand-binding beta B/beta C loop of PDZ1 and PDZ2 in the regulation of postsynaptic clustering, scaffolding, and localization of postsynaptic density-95.

    Nonaka M, Doi T, Fujiyoshi Y, Takemoto-Kimura S, Bito H

    The Journal of neuroscience : the official journal of the Society for Neuroscience   Vol. 26 ( 3 ) page： 763-74   2006.1

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1523/JNEUROSCI.2489-05.2006

    PubMed

  32. [Synaptic activity-dependent regulation of neuronal gene expression].

    Okuno H, Takemoto-Kimura S, Ohmae S, Okamura M, Ishihara N, Bito H

    Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme   Vol. 49 ( 3 Suppl ) page： 411-8   2004.2

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    Language：Japanese   Publishing type：Research paper (scientific journal)  

    PubMed

  33. Ca(2+)/CREB/CBP-dependent gene regulation: a shared mechanism critical in long-term synaptic plasticity and neuronal survival.

    Bito H, Takemoto-Kimura S

    Cell calcium   Vol. 34 ( 4-5 ) page： 425-30   2003.10

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    Language：English   Publishing type：Research paper (scientific journal)  

    PubMed

  34. Molecular cloning and characterization of CLICK-III/CaMKIgamma, a novel membrane-anchored neuronal Ca2+/calmodulin-dependent protein kinase (CaMK).

    Takemoto-Kimura S, Terai H, Takamoto M, Ohmae S, Kikumura S, Segi E, Arakawa Y, Furuyashiki T, Narumiya S, Bito H

    The Journal of biological chemistry   Vol. 278 ( 20 ) page： 18597-605   2003.5

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1074/jbc.M300578200

    PubMed

  35. Control of axon elongation via an SDF-1alpha/Rho/mDia pathway in cultured cerebellar granule neurons.

    Arakawa Y, Bito H, Furuyashiki T, Tsuji T, Takemoto-Kimura S, Kimura K, Nozaki K, Hashimoto N, Narumiya S

    The Journal of cell biology   Vol. 161 ( 2 ) page： 381-91   2003.4

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1083/jcb.200210149

    PubMed

  36. Multiple spatiotemporal modes of actin reorganization by NMDA receptors and voltage-gated Ca2+ channels.

    Furuyashiki T, Arakawa Y, Takemoto-Kimura S, Bito H, Narumiya S

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 99 ( 22 ) page： 14458-63   2002.10

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    Language：English   Publishing type：Research paper (scientific journal)  

    DOI： 10.1073/pnas.212148999

    PubMed

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Research Project for Joint Research, Competitive Funding, etc. 3

  1. カルシウムシグナル破綻に基づく精神疾患の分子細胞基盤解明と新規介入戦略の樹立

    2016.5

    脳科学研究戦略推進プログラム(脳プロ)  

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    Grant type：Competitive

  2. 脳深部微小神経回路を構成する細胞個性の機能的・分子的解読と情動制御への応用

    2015.10 - 2019.3

    戦略的創造研究推進事業（さきがけ） 

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    Grant type：Competitive

  3. リン酸化による大脳辺縁系情動回路修飾機構の解明

    2010.10 - 2014.3

    戦略的創造研究推進事業（さきがけ） 

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    Grant type：Competitive

To the head of Research Project for Joint Research, Competitive Funding, etc..▲

KAKENHI (Grants-in-Aid for Scientific Research) 12

  1. 神経細胞移動を制御するカルシウム依存的分子細胞機構の解明

    2016.4

    科学研究費補助金  基盤研究(B)

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    Authorship：Principal investigator 

  2. 分界条床核特定神経回路を介した不安生起機構

    2015.4 - 2017.3

    科学研究費補助金 

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    Authorship：Principal investigator 

  3. 神経回路形成を制御する新規カルシウム依存的リン酸化シグナリング機構の解明

    2011.4 - 2015.3

    科学研究費補助金  若手研究(A)

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    Authorship：Principal investigator 

  4. 脂質修飾型CaMキナーゼによる神経機能制御

    2008 - 2009

    科学研究費補助金  若手研究(B)

  5. アクチン動態を制御するCaMKK-CaMKIカスケードの神経機能解明

    2008 - 2009

    科学研究費補助金  若手研究(B)

  6. 蛋白質脂質修飾による膜挿入型CaMキナーゼCLICK-IIIの機能制御

    2006 - 2007

    科学研究費補助金  若手研究(B)

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    脳機能を担う神経回路の形成は、もともと球状である神経細胞が、細胞の骨組みである細胞骨格を利用して形を変化させ、樹状突起軸索と呼ばれる突起を発達させることで完成する。
    本研究課題では、CaMキナーゼCLICK-IIIの神経回路形成における機能を神経細胞培養のモデル系を用いて探索し、さらに本酵素の受ける蛋白質脂質修飾によって酵素機能がどのように修飾を受けるのか解明することを目的とした。
    まず、ラット大脳皮質神経細胞の樹状突起形成・伸展を培養下で観察する方法を確立した。本培養神経細胞において、RNAi法やノックアウトマウスを用いてCLICK-IIIの発現量を減少させると樹状突起形成が阻害され、逆に発現ベクターを用いて同発現を増加させると樹状突起形成が促進された。更に、本作用は神経栄養因子であるBDNFの効果発現においても寄与していることを明らかとした。分子レベルでは、CLICK-IIIが脂質と共有結合しラフト膜上に存在する結果、アクチン制御蛋白質Racを活性化することが、樹状突起形成作用の引き金となることを突き止め、樹状突起形成における蛋白質脂質修飾の重要性を分子レベルではじめて立証した。これらの成果は新たな樹状突起形成制御機構として注目され、Neuron誌にて掲載された。

  7. 新規膜挿入型CaMキナーゼCLICK-III/CaMKIγの神経機能解析

    2004 - 2005

    科学研究費補助金  若手研究(B)

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    本研究は、CaMKIファミリーに属する神経細胞特異的なCaMキナーゼ、CLICK-III/CaMKIγの、神経機能解明ならびにその分子機構の理解を目的とする。
    研究代表者は、前年度に本酵素がプレニル化ならびにパルミトイル化という複数の脂質修飾を受け膜アンカーされることを見出していたため、平成17年度は引き続き脂質修飾の制御ならびに生物学的意義についての研究を進めた。
    まず、2種類の脂質修飾であるプレニル化とパルミトイル化が互いに影響するか、各脂質修飾欠失変異体を用いて検討した。その結果、パルミトイル化を受けるためにはプレニル化を必要とする一方、パルミトイル化の有無によりプレニル化は影響されないことが分かり、細胞内において本酵素は、プレニル化、パルミトイル化を順序立って受けていることが示唆された。また、近年同定されたパルミトイル化酵素のうち、CLICK-IIIを基質とする候補分子を同定した。
    次に、CLICK-IIIの細胞生物学的機能について神経突起伸展のモデル細胞であるPC-12細胞を用いて検討した。CLICK-IIIを発現しないPC-12細胞にCLICK-IIIを発現させると、脱分極刺激によって誘導される突起伸展を促進することが分かった。更にこの作用は、脂質修飾欠失変異体においては減弱しており、脂質修飾が機能発現において重要な役割を果たすことが示唆された。
    以上の研究成果は...

  8. カルシウムシグナリングの神経回路形成における生理機能と脳病態への寄与

    Grant number：23K27486  2023.4 - 2026.3

    科学研究費助成事業  基盤研究(B)

    木村さやか

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    Authorship：Principal investigator 

    Grant amount：\18720000 （ Direct Cost: \14400000 、 Indirect Cost：\4320000 ）

    本研究では、神経カルシウムシグナリングの胎生期神経回路形成における生理機能を解明し、胎生期およびその後の脳病態への寄与を解明する。そのために胎生期を含む生涯において、神経カルシウムシグナリング活性化を担う主要な分子であるカルシウムチャネルに着目し、機能獲得型カルシウムチャネルを、時期選択的に脳内で挿入・欠失可能なマウス系統を開発し、神経カルシウムシグナリング破綻の個体病態モデルと位置付け研究を進める。このマウスモデル系統を用いることで、時期選択的な点変異の表現型への影響を初めて検証することが可能となり、特に神経回路形成が盛んな胎生期と出生後を区別して病態への寄与を検証する。

  9. Innovative nanotechnology for probing molecular landscapes in the brain

    Grant number：21H05089  2021.8 - 2024.3

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research  Grant-in-Aid for Transformative Research Areas (B)

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    Authorship：Coinvestigator(s) 

  10. ストレス性情動障害に関わる細胞外分子脳病態解析

    Grant number：21H05091  2021.8 - 2024.3

    科学研究費助成事業  学術変革領域研究(B)

    木村さやか, 宮田 茂雄

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    Authorship：Principal investigator 

    Grant amount：\40690000 （ Direct Cost: \31300000 、 Indirect Cost：\9390000 ）

    脳によって生起する情動（不安、恐怖、快楽など）は、生物が生存するうえで必要不可欠な生理機能である。現代社会における様々なストレスが一因となり、過度な情動の亢進や消失といった情動障害が生じ、うつ病や適応障害、不安障害をはじめとする精神疾患との病態に関与するとされる。本研究では、特に細胞外分子の変化を捉えるために、脳深部イメージング法やマイクロダイアリシス法などの分子脳生物学的手法を組み合わせ、ストレスに伴う情動障害の病態解明を目指し、モデルマウスを対象とした研究を推進する。

  11. カルシウム依存的神経回路形成の分子機構と脳機能制御

    Grant number：20H03339  2020.4 - 2023.3

    科学研究費助成事業  基盤研究(B)

    木村さやか

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    Authorship：Principal investigator 

    Grant amount：\17680000 （ Direct Cost: \13600000 、 Indirect Cost：\4080000 ）

    シナプス可塑性といった可塑的変化を制御する代表的経路であるCa2+依存的経路が、幼弱神経細胞においてどのような役割を果たすのか解明するため、申請者がこれまでに研究を進めてきたCa2+依存的リン酸化経路に着目した研究を行う。特にin vivoにおける機能を解明するため、独自に開発した遺伝子改変マウス、スライスイメージング法などを駆使し、多面的な検討を推進することで、カルシウム依存的神経回路形成に寄与する分子基盤を明らかとし、脳機能制御における重要性を解明する。

  12. Elucidation of calcium-dependent molecular and cellular mechanisms underlying the regulation of neuronal migration

    Grant number：16H04670  2016.4 - 2019.3

    Grants-in-Aid for Scientific Research  Grant-in-Aid for Scientific Research (B)

    Takemoto-Kimura Sayaka

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    Authorship：Principal investigator 

    Grant amount：\16770000 （ Direct Cost: \12900000 、 Indirect Cost：\3870000 ）

    A newly generated neuronal-committed cell, whose fate is to become a neuron, is located around the ventricle, and it relocates to suitable brain regions for the creation of functional neural circuits.It has been suggested that abnormal cell migration has a relationship with the etiology or is the basis of the neuropsychiatric disorders. To overcome these disorders, the understanding of the molecular mechanism of neuronal migration has been anticipated. In this study, we have focused on Ca2+-dependent protein kinases, among which the involvement of the axon and dendritic extension of cultured cerebral neurons was disclosed, and have shown their role in neuronal migration regulation. We also have identified its upstream Ca2+ source channel candidate during neuronal migration. Our findings in this study have extended our prior findings that can explain how and when Ca2+ signaling regulate brain development before the formation of the synapse.

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To the head of KAKENHI (Grants-in-Aid for Scientific Research).▲