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医学部 医学科 機能制御学講座薬理学分野 |
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Interaction between cardiac myosin-binding protein C and formin Fhod3 査読あり
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年5月
担当区分：筆頭著者 記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Proceedings of the National Academy of Sciences of the United States of America
© 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 査読あり
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年6月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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年10月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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年4月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Molecular Pain
Pulsed radiofrequency (PRF) therapy is one of the most common treatment options for neuropathic pain, albeit the underlying mechanism has not been hitherto elucidated. In this study, we investigated the efficacy and mechanism of PRF therapy on resiniferatoxin (RTX)-induced mechanical allodynia, which has been used as a model of postherpetic neuralgia (PHN). Adult male rats were intraperitoneally injected with a vehicle or RTX. Furthermore, PRF current was applied on a unilateral sciatic nerve in all RTX-treated rats. On both ipsilateral and contralateral sides, the paw mechanical withdrawal thresholds were examined and L4-6 dorsal root ganglia (DRG) were harvested. In the DRG of rats with RTX-induced mechanical allodynia, NaV1.7, a voltage-gated Na+ channel, was upregulated following the enhancement of extracellular signal-regulated kinase phosphorylation. Early PRF therapy, which was applied 1 week after RTX exposure, suppressed this NaV1.7 upregulation and showed an anti-allodynic effect; however, late PRF therapy, which was applied after 5 weeks of RTX exposure, failed to inhibit allodynia. Interestingly, late PRF therapy became effective after daily tramadol administration for 7 days, starting from 2 weeks after RTX exposure. Both early PRF therapy and late PRF therapy combined with early tramadol treatment suppressed NaV1.7 upregulation in the DRG of rats with RTX-induced mechanical allodynia. Therefore, NaV1.7 upregulation in DRG is related to the development of RTX-induced neuropathic pain; moreover, PRF therapy may be effective in the clinical management of patients with PHN via NaV1.7 upregulation inhibition.
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年11月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Cerebral Cortex
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.
講演・口頭発表等 【 表示 ／ 非表示 】
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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
開催年月日： 2020年9月14日 - 2020年9月16日
記述言語：日本語 会議種別：ポスター発表
開催地：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
開催年月日： 2020年11月21日
記述言語：日本語 会議種別：ポスター発表
開催地：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年11月1日
開催年月日： 2023年10月31日 - 2023年11月2日
記述言語：日本語 会議種別：ポスター発表
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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年11月1日
開催年月日： 2023年10月31日 - 2023年11月2日
記述言語：日本語 会議種別：ポスター発表
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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年6月24日
開催年月日： 2023年6月24日 - 2023年6月25日
記述言語：日本語 会議種別：ポスター発表
科研費（文科省・学振・厚労省）獲得実績 【 表示 ／ 非表示 】
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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
研究課題/領域番号：22K11754 2022年04月 - 2025年03月
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)
担当区分：研究代表者
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サルコメアは回転トルクを生み出すか？
研究課題/領域番号：22K19407 2022年04月 - 2024年03月
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、
担当区分：研究分担者
その他競争的資金獲得実績 【 表示 ／ 非表示 】
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骨格筋のターンオーバー機構からサルコペニアに挑む
2022年04月 - 2023年03月
宮崎大学 女性研究者の特色ある研究
担当区分：研究代表者
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Athenaリサーチアシスタント制度
2022年08月 - 2023年03月
宮崎大学 令和4年度「出産・育児・介護に関わる教職員に対する研究補助者雇用」
担当区分：研究代表者
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骨格筋収縮装置の恒常性維持とその破綻の分子機構
2019年04月 - 2020年03月
宮崎大学 戦略重点経費-女性研究者の特色ある研究
資金種別：競争的資金