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Affiliation |
Faculty of Medicine School of Medicine Department of Medical Sciences, Pharmacology |
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Research Assistant |
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External Link |
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KAGE Yohko
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Papers 【 display / non-display 】
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Interaction between cardiac myosin-binding protein C and formin Fhod3 Reviewed
Matsuyama S., Kage Y., Fujimoto N., Ushijima T., Tsuruda T., Kitamura K., Shiose A., Asada Y., Sumimoto H., Takeya R.
Proceedings of the National Academy of Sciences of the United States of America 115 ( 19 ) E4386 - E4395 2018.5
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)
© 2018 National Academy of Sciences. All rights reserved. Mutations in cardiac myosin-binding protein C (cMyBP-C) are a major cause of familial hypertrophic cardiomyopathy. Although cMyBP-C has been considered to regulate the cardiac function via cross-bridge arrangement at the C-zone of the myosin-containing A-band, the mechanism by which cMyBP-C functions remains unclear. We identified formin Fhod3, an actin organizer essential for the formation and maintenance of cardiac sarcomeres, as a cMyBP-C–binding protein. The cardiac-specific N-terminal Ig-like domain of cMyBP-C directly interacts with the cardiac-specific N-terminal region of Fhod3. The interaction seems to direct the localization of Fhod3 to the C-zone, since a noncardiac Fhod3 variant lacking the cMyBP-C–binding region failed to localize to the C-zone. Conversely, the cardiac variant of Fhod3 failed to localize to the C-zone in the cMyBP-C–null mice, which display a phenotype of hypertrophic cardiomyopathy. The cardiomyopathic phenotype of cMyBP-C–null mice was further exacerbated by Fhod3 overexpression with a defect of sarcomere integrity, whereas that was partially ameliorated by a reduction in the Fhod3 protein levels, suggesting that Fhod3 has a deleterious effect on cardiac function under cMyBP-C–null conditions where Fhod3 is aberrantly mislocalized. Together, these findings suggest the possibility that Fhod3 contributes to the pathogenesis of cMyBP-C–related cardiomyopathy and that Fhod3 is critically involved in cMyBP-C–mediated regulation of cardiac function via direct interaction.
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Role of Src homology 3 domains in assembly and activation of the phagocyte NADPH oxidase Reviewed
Sumimoto H., Kage Y., Nunoi H., Sasaki H., Nose T., Fukumaki Y., Ohno M., Minakami S., Takeshige K.
Proceedings of the National Academy of Sciences of the United States of America 91 ( 12 ) 5345 - 5349 1994.6
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Proceedings of the National Academy of Sciences of the United States of America
The phagocyte NADPH oxidase, dormant in resting cells, is activated during phagocytosis to produce superoxide, a precursor of microbicidal oxidants. The activated oxidase is a complex of membrane-integrated cytochrome b 558 , composed of 91-kDa (gp91(phox)) and 22-kDa (p22(phox)) subunits, and two cytosolic factors (p47(phox) and p67(phox)), each containing two Src homology 3 (SH3) domains. Here we show that the region of the tandem SH3 domains of p47(phox) (p47-SH3) expressed as a glutathione S-transferase fusion protein inhibits the superoxide production in a cell-free system, indicating involvement of the domains in the activation. Furthermore, we find that arachidonic acid and sodium dodecyl sulfate, activators of the oxidase in vitro, cause exposure of p47-SH3, which has probably been masked by the C- terminal region of this protein in a resting state. The unmasking of p47-SH3 appears to play a crucial role in the assembly of the oxidase components, because p47-SH3 binds to both p22(phox) and p67(phox) but fails to interact with a mutant p22(phox) carrying a Pro-156 → Gln substitution in a proline- rich region, which has been found in a patient with chronic granulomatous disease. Based on the observations, we propose a signal-transducing mechanism whereby normally inaccessible SH3 domains become exposed upon activation to interact with their target proteins.
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Maruta T., Hidaka K., Kouroki S., Koshida T., Kurogi M., Kage Y., Mizuno S., Shirasaka T., Yanagita T., Takahashi S., Takeya R., Tsuneyoshi I.
PLoS ONE 17 ( 10 October ) e0275751 2022.10
Language：English Publishing type：Research paper (scientific journal) Publisher：PLoS ONE
In small and large spinal dorsal root ganglion neurons, subtypes of voltage-gated sodium channels, such as NaV1.7, NaV1.8, and NaV1.9 are expressed with characteristically localized and may play different roles in pain transmission and intractable pain development. Selective stimulation of each specific subtype in vivo may elucidate its role of each subtype in pain. So far, this has been difficult with current technology. However, Optogenetics, a recently developed technique, has enabled selective activation or inhibition of specific neural circulation in vivo. Moreover, optogenetics had even been used to selectively excite NaV1.8-expressing dorsal root ganglion neurons to induce nocifensive behavior. In recent years, genetic modification technologies such as CRISPR/Cas9 have advanced, and various knock-in mice can be easily generated using such technology. We aimed to investigate the effects of selective optogenetic activation of NaV1.7-expressing afferents on mouse behavior. We used CRISPR/Cas9-mediated homologous recombination to generate bicistronic NaV1.7–iCre knock-in mice, which express iCre recombinase under the endogenous NaV1.7 gene promoter without disrupting NaV1.7. The Cre-driver mice were crossed with channelrhodopsin-2 (ChR2) Cre-reporter Ai32 mice to obtain NaV1.7iCre/+;Ai32/+, NaV1.7iCre/iCre;Ai32/+, NaV1.7iCre/+;Ai32/Ai32, and NaV1.7iCre/iCre;Ai32/Ai32 mice. Compared with wild–type mice behavior, no differences were observed in the behaviors associated with mechanical and thermal stimuli exhibited by mice of the aforementioned genotypes, indicating that the endogenous NaV1.7 gene was not affected by the targeted insertion of iCre. Blue light irradiation to the hind paw induced paw withdrawal by mice of all genotypes in a light power-dependent manner. The threshold and incidence of paw withdrawal and aversive behavior in a blue-lit room were dependent on ChR2 expression level; the strongest response was observed in NaV1.7iCre/iCre;Ai32/Ai32 mice. Thus, we developed a non-invasive pain model in which peripheral nociceptors were optically activated in free-moving transgenic NaV1.7–ChR2 mice.
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Hidaka K., Maruta T., Koshida T., Kurogi M., Kage Y., Kouroki S., Shirasaka T., Takeya R., Tsuneyoshi I.
Molecular Pain 18 1 - 12 2022.4
Language：English Publishing type：Research paper (scientific journal)
DOI： 10.1177/17448069221089784
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Sulistomo HW, Nemoto T, Kage Y, Fujii H, Uchida T, Takamiya K, Sumimoto H, Kataoka H, Bito H, Takeya R
Cerebral cortex (New York, N.Y. : 1991) 31 ( 4 ) 2205 - 2219 2020.11
Language：English Publishing type：Research paper (scientific journal)
Changes in the shape and size of the dendritic spines are critical for synaptic transmission. These morphological changes depend on dynamic assembly of the actin cytoskeleton and occur differently in various types of neurons. However, how the actin dynamics are regulated in a neuronal cell type-specific manner remains largely unknown. We show that Fhod3, a member of the formin family proteins that mediate F-actin assembly, controls the dendritic spine morphogenesis of specific subpopulations of cerebrocortical pyramidal neurons. Fhod3 is expressed specifically in excitatory pyramidal neurons within layers II/III and V of restricted areas of the mouse cerebral cortex. Immunohistochemical and biochemical analyses revealed the accumulation of Fhod3 in postsynaptic spines. Although targeted deletion of Fhod3 in the brain did not lead to any defects in the gross or histological appearance of the brain, the dendritic spines in pyramidal neurons within presumptive Fhod3-positive areas were morphologically abnormal. In primary cultures prepared from the Fhod3-depleted cortex, defects in spine morphology were only detected in Fhod3 promoter-active cells, a small population of pyramidal neurons, and not in Fhod3 promoter-negative pyramidal neurons. Thus, Fhod3 plays a crucial role in dendritic spine morphogenesis only in a specific population of pyramidal neurons in a cell type-specific manner.
Presentations 【 display / non-display 】
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マウス大脳皮質におけるフォルミン蛋白質の発現パターン
鹿毛陽子, Hikmawan Wahyu Sulistomo, 武谷立
第93回日本生化学会 (京都（WEB開催）) 日本生化学会
Event date： 2020.9.14 - 2020.9.16
Language：Japanese Presentation type：Poster presentation
Venue：京都（WEB開催）
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アクチン重合制御因子フォルミン蛋白質のマウス大脳皮質における発現
鹿毛陽子, Hikmawan Wahyu Sulistomo, 武谷立
第73回日本薬理学会西南部会 (熊本県（WEB開催）) 日本薬理学会西南部会
Event date： 2020.11.21
Language：Japanese Presentation type：Poster presentation
Venue：熊本県（WEB開催）
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サルコメア恒常性の破綻がもたらす心筋細胞の形態変化と細胞死.
鹿毛陽子，阪口修平，武谷 立
第96回日本生化学会大会 2023.11.1
Event date： 2023.10.31 - 2023.11.2
Language：Japanese Presentation type：Poster presentation
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舌筋におけるフォルミン蛋白質Fhod3の発現と分布.
中川光，鹿毛 陽子，武谷立
第96回日本生化学会大会 2023.11.1
Event date： 2023.10.31 - 2023.11.2
Language：Japanese Presentation type：Poster presentation
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心筋細胞におけるサルコメア崩壊がもたらす形態変化と細胞死.
鹿毛陽子，阪口修平, 武谷立
令和5年度日本生化学会九州支部例会 2023.6.24
Event date： 2023.6.24 - 2023.6.25
Language：Japanese Presentation type：Poster presentation
Grant-in-Aid for Scientific Research 【 display / non-display 】
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骨格筋サルコメアの恒常性維持機構ならびにその破綻として捉えるサルコペニア
Grant number：22K11754 2022.04 - 2025.03
独立行政法人日本学術振興会 科学研究費補助金 基盤研究(C)
Authorship：Principal investigator
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サルコメアは回転トルクを生み出すか？
Grant number：22K19407 2022.04 - 2024.03
独立行政法人日本学術振興会 科学研究費補助金 挑戦的研究（萌芽）
武谷 立、
Authorship：Coinvestigator(s)