九州大学 研究者情報
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兼松 隆(かねまつ たかし) データ更新日:2021.07.01

教授 /  歯学研究院 歯学部門 口腔常態制御学講座


主な研究テーマ
抗腫瘍免疫を賦活化する新しい制癌シグナル分子の機能解明研究
キーワード:抗腫瘍免疫
2021.04~2024.03.
肥満による末梢炎症と2型糖尿病の解析研究
キーワード:肥満, 糖尿病, 末梢炎症, miRNA
2019.04~2022.03.
3型糖尿病としてのアルツハイマー病に関する研究
キーワード:糖尿病, アルツハイマー病, 脳内炎症, ミクログリア
2019.04~2022.03.
オートファジーと新規分子PRIP
キーワード:オートファジー
2004.08~2015.03.
インスリン分泌における新規分子PRIPの役割解明研究
キーワード:インスリン分泌
2005.04~2016.03.
肥満と新規分子PRIPの関わり
キーワード:肥満
2005.04.
GABA(A)受容体構築の分子機構解明
キーワード:GABA(A)受容体
2000.04~2017.03.
PRIP分子のイノシトール三リン酸情報伝達系における役割解明
キーワード:PRIP イノシトール三リン酸
2000.04~2004.03.
従事しているプロジェクト研究
抗腫瘍免疫を賦活化する新しい制癌シグナル分子の機能解明研究
2021.04~2024.03, 代表者:兼松隆, 九州大学.
肥満による末梢炎症と2型糖尿病の解析研究
2019.04~2022.03, 代表者:兼松隆, 九州大学.
3型糖尿病としてのアルツハイマー病に関する研究
2019.04~2022.03, 代表者:兼松隆, 九州大学.
2光子顕微鏡による新奇分子を介した開口放出制御の解明研究
2008.04~2009.03, 代表者:兼松 隆, 九州大学, 自然科学研究機構・生理学研究所.
GABA(A)受容体の膜発現量調節の分子機構解明研究
2008.04~2009.03, 代表者:平田雅人, 九州大学, 自然科学研究機構・生理学研究所.
GABAシグナリングにおlける新規分子PRIPの役割解明
2007.04~2007.12, 代表者:平田雅人, 九州大学, 自然科学研究機構・生理学研究所.
新規分子(PRIP)の機能解明研究
2006.04~2007.03, 代表者:平田雅人, 九州大学, 自然科学研究機構・生理学研究所.
新規分子(PRIP)の機能解明研究
2005.04~2006.03, 代表者:平田雅人, 九州大学, 自然科学研究機構・生理学研究所.
研究業績
主要著書
主要原著論文
1. Satoshi Asano, Yasuka Ikura, Mitsuki Nishimoto, Yosuke Yamawaki, Kozue Hamao, Keiju Kamijo, Masato Hirata, Takashi Kanematsu, Phospholipase C-related catalytically inactive protein regulates cytokinesis by protecting phosphatidylinositol 4,5-bisphosphate from metabolism in the cleavage furrow, Scientific reports, 10.1038/s41598-019-49156-3, 9, 1, 2019.12, [URL], Cytokinesis is initiated by the formation and ingression of the cleavage furrow. Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] accumulation followed by RhoA translocation to the cleavage furrow are prerequisites for cytokinesis progression. Here, we investigated whether phospholipase C (PLC)-related catalytically inactive protein (PRIP), a metabolic modulator of PI(4,5)P2, regulates PI(4,5)P2-mediated cytokinesis. We found that PRIP localised to the cleavage furrow during cytokinesis. Moreover, HeLa cells with silenced PRIP displayed abnormal cytokinesis. Importantly, PI(4,5)P2 accumulation at the cleavage furrow, as well as the localisation of RhoA and phospho-myosin II regulatory light chain to the cleavage furrow, were reduced in PRIP-silenced cells. The overexpression of oculocerebrorenal syndrome of Lowe-1 (OCRL1), a phosphatidylinositol-5-phosphatase, in cells decreased PI(4,5)P2 levels during early cytokinesis and resulted in cytokinesis abnormalities. However, these abnormal cytokinesis phenotypes were ameliorated by the co-expression of PRIP but not by co-expression of a PI(4,5)P2-unbound PRIP mutant. Collectively, our results indicate that PRIP is a component at the cleavage furrow that maintains PI(4,5)P2 metabolism and regulates RhoA-dependent progression of cytokinesis. Thus, we propose that PRIP regulates phosphoinositide metabolism correctively and mediates normal cytokinesis progression..
2. Yosuke Yamawaki, Satomi Shirawachi, Akiko Mizokami, Kanako Nozaki, Hikaru Ito, Satoshi Asano, Kana Oue, Hidenori Aizawa, Shigeto Yamawaki, Masato Hirata, Takashi Kanematsu, Phospholipase C-related catalytically inactive protein regulates lipopolysaccharide-induced hypothalamic inflammation-mediated anorexia in mice, Neurochemistry International, 10.1016/j.neuint.2019.104563, 131, 2019.12, [URL], Peripheral lipopolysaccharide (LPS) injection induces systemic inflammation through the activation of the inhibitor of nuclear factor kappa B (NF-κB) kinase (IKK)/NF-κB signaling pathway, which promotes brain dysfunction resulting in conditions including anorexia. LPS-mediated reduction of food intake is associated with activation of NF-κB signaling and phosphorylation of the transcription factor signal transducer and activator of transcription 3 (STAT3) in the hypothalamus. We recently reported phospholipase C-related catalytically inactive protein (PRIP) as a new negative regulator of phosphatidylinositol 3-kinase/AKT signaling. AKT regulates the IKK/NF-κB signaling pathway; therefore, this study aimed to investigate the role of PRIP/AKT signaling in LPS-mediated neuroinflammation-induced anorexia. PRIP gene (Prip1 and Prip2) knockout (Prip-KO) mice intraperitoneally (ip) administered with LPS exhibited increased anorexia responses compared with wild-type (WT) controls. Although few differences were observed between WT and Prip-KO mice in LPS-elicited plasma pro-inflammatory cytokine elevation, hypothalamic pro-inflammatory cytokines were significantly upregulated in Prip-KO rather than WT mice. Hypothalamic AKT and IKK phosphorylation and IκB degradation were significantly increased in Prip-KO rather than WT mice, indicating further promotion of AKT-mediated NF-κB signaling. Consistently, hypothalamic STAT3 was further phosphorylated in Prip-KO rather than WT mice. Furthermore, suppressor of cytokine signaling 3 (Socs3), a negative feedback regulator for STAT3 signaling, and cyclooxogenase-2 (Cox2), a candidate molecule in LPS-induced anorexigenic responses, were upregulated in the hypothalamus in Prip-KO rather than WT mice. Pro-inflammatory cytokines were upregulated in hypothalamic microglia isolated from Prip-KO rather than WT mice. Together, these findings indicate that PRIP negatively regulates LPS-induced anorexia caused by pro-inflammatory cytokine expression in the hypothalamus, which is mediated by AKT-activated NF-κB signaling. Importantly, hypothalamic microglia participate in this PRIP-mediated process. Elucidation of PRIP-mediated neuroinflammatory responses may provide novel insights into the pathophysiology of many brain dysfunctions..
3. Satoshi Asano, Yuri Taniguchi, Yosuke Yamawaki, Jing Gao, Kae Harada, Hiroshi Takeuchi, Masato Hirata, Takashi Kanematsu, Suppression of cell migration by phospholipase C-related catalytically inactive protein-dependent modulation of PI3K signalling, Scientific reports, 10.1038/s41598-017-05908-7, 7, 1, 2017.12, [URL], The metabolic processes of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] into PI(3,4,5)P3 and the subsequent PI(3,4,5)P3 signalling are involved in cell migration. Dysfunctions in the control of this pathway can cause human cancer cell migration and metastatic growth. Here we investigated whether phospholipase C-related catalytically inactive protein (PRIP), a PI(4,5)P2-binding protein, regulates cancer cell migration. PRIP overexpression in MCF-7 and BT-549 human breast cancer cells inhibited cell migration in vitro and metastasis development in vivo. Overexpression of the PRIP pleckstrin homology domain, a PI(4,5)P2 binding motif, in MCF-7 cells caused significant suppression of cell migration. Consistent with these results, in comparison with wild-type cells, Prip-deficient mouse embryonic fibroblasts exhibited increased cell migration, and this was significantly attenuated upon transfection with a siRNA targeting p110α, a catalytic subunit of class I phosphoinositide 3-kinases (PI3Ks). PI(3,4,5)P3 production was decreased in Prip-overexpressing MCF-7 and BT-549 cells. PI3K binding to PI(4,5)P2 was significantly inhibited by recombinant PRIP in vitro, and thus the activity of PI3K was downregulated. Collectively, PRIP regulates the production of PI(3,4,5)P3 from PI(4,5)P2 by PI3K, and the suppressor activity of PRIP in PI(4,5)P2 metabolism regulates the tumour migration, suggesting PRIP as a promising target for protection against metastatic progression..
4. Kana Oue, Jun Zhang, Kae Harada-Hada, Satoshi Asano, Yosuke Yamawaki, Masaki Hayashiuchi, Hisako Furusho, Takashi Takata, Masahiro Irifune, Masato Hirata, Takashi Kanematsu, Phospholipase C-related Catalytically Inactive Protein Is a New Modulator of Thermogenesis Promoted by β-Adrenergic Receptors in Brown Adipocytes, Journal of Biological Chemistry, 10.1074/jbc.M115.705723, 291, 8, 4185-4196, 2016.02, [URL], Phospholipase C-related catalytically inactive protein (PRIP) was first identified as an inositol 1,4,5-trisphosphate-binding protein, and was later found to be involved in a variety of cellular events, particularly those related to protein phosphatases. We previously reported that Prip knock-out (KO) mice exhibit a lean phenotype with a small amount of white adipose tissue. In the present study, we examined whether PRIP is involved in energy metabolism, which could explain the lean phenotype, using high-fat diet (HFD)-fed mice. Prip-KO mice showed resistance to HFD-induced obesity, resulting in protection from glucose metabolism dysfunction and insulin resistance. Energy expenditure and body temperature at night were significantly higher in Prip-KO mice than in wild-type mice. Gene and protein expression of uncoupling protein 1 (UCP1), a thermogenic protein, was up-regulated in Prip-KO brown adipocytes in ther-moneutral or cold environments. These phenotypes were caused by the promotion of lipolysis in Prip-KO brown adipocytes, which is triggered by up-regulation of phosphorylation of the lipolysis-related proteins hormone-sensitive lipase and perilipin, followed by activation of UCP1 and/or up-regulation of thermogenesis-related genes (e.g. peroxisome proliferator-activated receptor-γ coactivator-1α). The results indicate that PRIP negatively regulates UCP1-mediated thermogenesis in brown adipocytes..
5. Satoshi Asano, Tomomi Nemoto, Tomoya Kitayama, Kae Harada, Jun Zhang, Kana Harada, Isei Tanida, Masato Hirata, Takashi Kanematsu, Phospholipase C-related catalytically inactive protein (PRIP) controls KIF5B-mediated insulin secretion, Biology Open, 10.1242/bio.20147591, 3, 6, 463-474, 2014.06, [URL], We previously reported that phospholipase C-related catalytically inactive protein (PRIP)-knockout mice exhibited hyperinsulinemia. Here, we investigated the role of PRIP in insulin granule exocytosis using Prip-knockdown mouse insulinoma (MIN6) cells. Insulin release from Prip-knockdown MIN6 cells was higher than that from control cells, and Prip knockdown facilitated movement of GFP-phogrinlabeled insulin secretory vesicles. Double-immunofluorescent staining and density step-gradient analyses showed that the KIF5B motor protein co-localized with insulin vesicles in Prip-knockdown MIN6 cells. Knockdown of GABAA -receptor-associated protein (GABARAP), a microtubule-associated PRIP-binding partner, by Gabarap silencing in MIN6 cells reduced the co-localization of insulin vesicles with KIF5B and the movement of vesicles, resulting in decreased insulin secretion. However, the co-localization of KIF5B with microtubules was not altered in Prip- and Gabarap-knockdown cells. The presence of unbound GABARAP, freed either by an interference peptide or by Prip silencing, in MIN6 cells enhanced the co-localization of insulin vesicles with microtubules and promoted vesicle mobility. Taken together, these data demonstrate that PRIP and GABARAP function in a complex to regulate KIF5B-mediated insulin secretion, providing new insights into insulin exocytic mechanisms..
6. Toshiya Okumura, Kae Harada, Kana Oue, Jun Zhang, Satoshi Asano, Masaki Hayashiuchi, Akiko Mizokami, Hiroto Tanaka, Masahiro Irifune, Nobuyuki Kamata, Masato Hirata, Takashi Kanematsu, Phospholipase C-related catalytically inactive protein (PRIP) regulates lipolysis in adipose tissue by modulating the phosphorylation of hormone-sensitive lipase, PloS one, 10.1371/journal.pone.0100559, 9, 6, 2014.06, [URL], Phosphorylation of hormone-sensitive lipase (HSL) and perilipin by protein kinase A (PKA) promotes the hydrolysis of lipids in adipocytes. Although activation of lipolysis by PKA has been well studied, inactivation via protein phosphatases is poorly understood. Here, we investigated whether phospholipase C-related catalytically inactive protein (PRIP), a binding partner for protein phosphatase 1 and protein phosphatase 2A (PP2A), is involved in lipolysis by regulating phosphatase activity. PRIP knockout (PRIP-KO) mice displayed reduced body-fat mass as compared with wild-type mice fed with standard chow ad libitum. Most other organs appeared normal, suggesting that mutant mice had aberrant fat metabolism in adipocytes. HSL in PRIP-KO adipose tissue was highly phosphorylated compared to that in wild-type mice. Starvation of wild-type mice or stimulation of adipose tissue explants with the catabolic hormone, adrenaline, translocated both PRIP and PP2A from the cytosol to lipid droplets, but the translocation of PP2A was significantly reduced in PRIP-KO adipocytes. Consistently, the phosphatase activity associated with lipid droplet fraction in PRIP -KO adipocytes was significantly reduced and was independent of adrenaline stimulation. Lipolysis activity, as assessed by measurement of non-esterified fatty acids and glycerol, was higher in PRIP-KO adipocytes. When wild-type adipocytes were treated with a phosphatase inhibitor, they showed a high lipolysis activity at the similar level to PRIP-KO adipocytes. Collectively, these results suggest that PRIP promotes the translocation of phosphatases to lipid droplets to trigger the dephosphorylation of HSL and perilipin A, thus reducing PKA-mediated lipolysis. Copyright:.
7. Kae Harada-Hada, Kana Harada, Fuminori Kato, Junzo Hisatsune, Isei Tanida, Michinaga Ogawa, Satoshi Asano, Motoyuki Sugai, Masato Hirata, Takashi Kanematsu, Phospholipase C-related catalytically inactive protein participates in the autophagic elimination of Staphylococcus aureus infecting mouse embryonic fibroblasts, PloS one, 10.1371/journal.pone.0098285, 9, 5, 2014.05, [URL], Autophagy is an intrinsic host defense system that recognizes and eliminates invading bacterial pathogens. We have identified microtubule- associated protein 1 light chain 3 (LC3), a hallmark of autophagy, as a binding partner of phospholipase C-related catalytically inactive protein (PRIP) that was originally identified as an inositol trisphosphatebinding protein. Here, we investigated the involvement of PRIP in the autophagic elimination of Staphylococcus aureus in infected mouse embryonic fibroblasts (MEFs). We observed significantly more LC3-positive autophagosome-like vacuoles enclosing an increased number of S. aureus cells in PRIP-deficient MEFs than control MEFs, 3 h and 4.5 h post infection, suggesting that S. aureus proliferates in LC3-positive autophagosome-like vacuoles in PRIP-deficient MEFs. We performed autophagic flux analysis using an mRFP-GFP-tagged LC3 plasmid and found that autophagosome maturation is significantly inhibited in PRIP-deficient MEFs. Furthermore, acidification of autophagosomes was significantly inhibited in PRIP-deficient MEFs compared to the wild-type MEFs, as determined by LysoTracker staining and time-lapse image analysis performed using mRFP-GFP-tagged LC3. Taken together, our data show that PRIP is required for the fusion of S. aureus-containing autophagosome-like vacuoles with lysosomes, indicating that PRIP is a novel modulator in the regulation of the innate immune system in non-professional phagocytic host cells. Copyright:.
8. Tomoya Kitayama, Katsuya Morita, Rizia Sultana, Nami Kikushige, Keisuke Mgita, Shinya Ueno, Masato Hirata, Takashi Kanematsu, Phospholipase C-related but catalytically inactive protein modulates pain behavior in a neuropathic pain model in mice, Molecular Pain, 10.1186/1744-8069-9-23, 9, 1, 2013.05, [URL], Background: An inositol 1,4,5-trisphosphate binding protein, comprising 2 isoforms termed PRIP-1 and PRIP-2, was identified as a novel modulator for GABAA receptor trafficking. It has been reported that naive PRIP-1 knockout mice have hyperalgesic responses.Findings: To determine the involvement of PRIP in pain sensation, a hind paw withdrawal test was performed before and after partial sciatic nerve ligation (PSNL) in PRIP-1 and PRIP-2 double knockout (DKO) mice. We found that naive DKO mice exhibited normal pain sensitivity. However, DKO mice that underwent PSNL surgery showed increased ipsilateral paw withdrawal threshold. To further investigate the inverse phenotype in PRIP-1 KO and DKO mice, we produced mice with specific siRNA-mediated knockdown of PRIPs in the spinal cord. Consistent with the phenotypes of KO mice, PRIP-1 knockdown mice showed allodynia, while PRIP double knockdown (DKD) mice with PSNL showed decreased pain-related behavior. This indicates that reduced expression of both PRIPs in the spinal cord induces resistance towards a painful sensation. GABAA receptor subunit expression pattern was similar between PRIP-1 KO and DKO spinal cord, while expression of K+-Cl--cotransporter-2 (KCC2), which controls the balance of neuronal excitation and inhibition, was significantly upregulated in DKO mice. Furthermore, in the DKD PSNL model, an inhibitor-induced KCC2 inhibition exhibited an altered phenotype from painless to painful sensations.Conclusions: Suppressed expression of PRIPs induces an elevated expression of KCC2 in the spinal cord, resulting in inhibition of nociception and amelioration of neuropathic pain in DKO mice..
9. Hisanori Umebayashi, Akiko Mizokami, Miho Matsuda, Kae Harada, Hiroshi Takeuchi, Isei Tanida, Masato Hirata, Takashi Kanematsu, Phospholipase C-related catalytically inactive protein, a novel microtubule-associated protein 1 light chain 3-binding protein, negatively regulates autophagosome formation, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2013.01.119, 432, 2, 268-274, 2013.03, [URL], Upon starvation, cells undergo autophagy, an intracellular bulk-degradation process, to provide the required nutrients. Here, we observed that phospholipase C-related catalytically inactive protein (PRIP) binds to microtubule-associated protein 1 light chain 3 (LC3), a mammalian autophagy-related initiator that regulates the autophagy pathway. Then, we examined the involvement of PRIP in the nutrient depletion-induced autophagy pathway. Enhanced colocalization of PRIP with LC3 was clearly seen in nutrient-starved mouse embryonic fibroblasts under a fluorescent microscope, and interaction of the proteins was revealed by immunoprecipitation experiments with an anti-LC3 antibody. Under starvation conditions, there were more green fluorescent protein fused-LC3 dots in mouse embryonic fibroblasts from PRIP-deficient mice than in fibroblasts from wild type cells. The formation of new dots in a single cell increased, as assessed by time-lapse microscopy. Furthermore, the increase in autophagosome formation in PRIP-deficient cells was notably inhibited by exogenously overexpressed PRIP. Taken together, PRIP is a novel LC3-binding protein that acts as a negative modulator of autophagosome formation..
10. Akiko Mizokami, Hiroto Tanaka, Hitoshi Ishibashi, Hisanori Umebayashi, Kiyoko Fukami, Tadaomi Takenawa, Keiichi I. Nakayama, Takeshi Yokoyama, Junichi Nabekura, Takashi Kanematsu, Masato Hirata, GABAA receptor subunit alteration-dependent diazepam insensitivity in the cerebellum of phospholipase C-related inactive protein knockout mice, Journal of Neurochemistry, 10.1111/j.1471-4159.2010.06754.x, 114, 1, 302-310, 2010.07, [URL], The GABAA receptor, a pentamer composed predominantly of α, β, and γ subunits, mediates fast inhibitory synaptic transmission. We have previously reported that phospholipase C-related inactive protein (PRIP) is a modulator of GABAA receptor trafficking and that knockout (KO) mice exhibit a diazepam-insensitive phenotype in the hippocampus. The α subunit affects diazepam sensitivity; α1, 2, 3, and 5 subunits assemble with any form of β and the γ2 subunits to produce diazepam-sensitive receptors, whereas α4 or α6/β/γ2 receptors are diazepam-insensitive. Here, we investigated how PRIP is implicated in the diazepam-insensitive phenotype using cerebellar granule cells in animals expressing predominantly the α6 subunit. The expression of α1/β/γ2 diazepam-sensitive receptors was decreased in the PRIP-1 and 2 double KO cerebellum without any change in the total number of benzodiazepine-binding sites as assessed by radioligand-binding assay. Since levels of the α6 subunit were increased, the α1/β/γ2 receptors might be replaced with α6 subunit-containing receptors. Then, we further performed autoradiographic and electrophysiologic analyses. These results suggest that the expression of α6/δ receptors was decreased in cerebellar granule neurons, while that of α6/γ2 receptors was increased. PRIP-1 and 2 double KO mice exhibit a diazepam-insensitive phenotype because of a decrease in diazepam-sensitive (α1/γ2) and increase in diazepam-insensitive (α6/γ2) GABAA receptors in the cerebellar granule cells..
11. Makoto Fujii, Takashi Kanematsu, Hitoshi Ishibashi, Kiyoko Fukami, Tadaomi Takenawa, Keiichi I. Nakayama, Stephen J. Moss, Junichi Nabekura, Masato Hirata, Phospholipase C-related but catalytically inactive protein is required for insulin-induced cell surface expression of γ-aminobutyric acid type A receptors, Journal of Biological Chemistry, 10.1074/jbc.M109.070045, 285, 7, 4837-4846, 2010.02, [URL], The γ-aminobutyric acid type A (GABAA) receptors play a pivotal role in fast synaptic inhibition in the central nervous system. One of the key factors for determining synaptic strength is the number of receptors on the postsynaptic membrane, which is maintained by the balance between cell surface insertion and endocytosis of the receptors. In this study, we investigated whether phospholipase C-related but catalytically inactive protein (PRIP) is involved in insulin-induced GABAA receptor insertion. Insulin potentiated the GABA-induced Cl- current (IGABA) by about 30% in wild-type neurons, but not in PRIP1 and PRIP2 double-knock-out (DKO) neurons, suggesting that PRIP is involved in insulin-induced potentiation. The phosphorylation level of the GABAA receptor β-subunit was increased by about 30% in the wild-type neurons but not in the mutant neurons, which were similar to the changes observed in IGABA. We also revealed that PRIP recruited active Akt to the GABAA receptors by forming a ternary complex under insulin stimulation. The disruption of the binding between PRIP and the GABAA receptor β-subunit by PRIP interference peptide attenuated the insulin potentiation of IGABA. Taken together, these results suggest that PRIP is involved in insulin-induced GABAA receptor insertion by recruiting active Akt to the receptor complex..
12. Takashi Kanematsu, Makoto Fujii, Akiko Mizokami, Josef T. Kittler, Junichi Nabekura, Stephen J. Moss, Masato Hirata, Phospholipase C-related inactive protein is implicated in the constitutive internalization of GABAA receptors mediated by clathrin and AP2 adaptor complex, Journal of Neurochemistry, 10.1111/j.1471-4159.2006.04399.x, 101, 4, 898-905, 2007.05, [URL], A mechanism for regulating the strength of synaptic inhibition is enabled by altering the number of GABAA receptors available at the cell surface. Clathrin and adaptor protein 2 (AP2) complex-mediated endocytosis is known to play a fundamental role in regulating cell surface GABAA receptor numbers. Very recently, we have elucidated that phospholipase C-related catalytically inactive protein (PRIP) molecules are involved in the phosphorylation-dependent regulation of the internalization of GABAA receptors through association with receptor β subunits and protein phosphatases. In this study, we examined the implications of PRIP molecules in clathrin-mediated constitutive GABAA receptor endocytosis, independent of phospho-regulation. We performed a constitutive receptor internalization assay using human embryonic kidney 293 (HEK293) cells transiently expressed with GABAA receptor α/β/γ subunits and PRIP. PRIP was internalized together with GABAA receptors, and the process was inhibited by PRIP-binding peptide which blocks PRIP binding to β subunits. The clathrin heavy chain, μ2 and β2 subunits of AP2 and PRIP-1, were complexed with GABAA receptor in brain extract as analyzed by co-immunoprecipitation assay using anti-PRIP-1 and anti-β2/3 GABAA receptor antibody or by pull-down assay using β subunits of GABAA receptor. These results indicate that PRIP is primarily implicated in the constitutive internalization of GABAA receptor that requires clathrin and AP2 protein complex..
13. Akiko Mizokami, Takashi Kanematsu, Hitoshi Ishibashi, Taku Yamaguchi, Isei Tanida, Kei Takenaka, Keiichi I. Nakayama, Kiyoko Fukami, Tadaomi Takenawa, Eiki Kominami, Stephen J. Moss, Tsuneyuki Yamamoto, Junichi Nabekura, Masato Hirata, Phosholipase C-related inactive protein is involved in trafficking of γ2 subunit-containing GABAA receptors to the cell surface, Journal of Neuroscience, 10.1523/JNEUROSCI.3155-06.2007, 27, 7, 1692-1701, 2007.02, [URL], The subunit composition of GABAA receptors is known to be associated with distinct physiological and pharmacological properties. Previous studies that used phospholipase C-related inactive protein type 1 knock-out (PRIP-1 KO) mice revealed that PRIP-1 is involved in the assembly and/or the trafficking of γ2 subunit-containing GABAA receptors. There are two PRIP genes in mammals; thus the roles of PRIP-1 might be compensated partly by those of PRIP-2 in PRIP-1 KO mice. Here we used PRIP-1 and PRIP-2 double knock-out (PRIP-DKO) mice and examined the roles for PRIP in regulating the trafficking of GABAA receptors. Consistent with previous results, sensitivity to diazepam was reduced in electrophysiological and behavioral analyses of PRIP-DKO mice, suggesting an alteration of γ2 subunit-containing GABAA receptors. The surface numbers of diazepam binding sites (α/γ2 subunits) assessed by [3H]flumazenil binding were reduced in the PRIP-DKO mice as compared with those of wild-type mice, whereas the cell surface GABA binding sites (α/β subunits, assessed by [3H]muscimol binding) were increased in PRIP-DKO mice. The association between GABAA receptors and GABAA receptor-associated protein (GABARAP) was reduced significantly in PRIP-DKO neurons. Disruption of the direct interaction between PRIP and GABAA receptor β subunits via the use of a peptide corresponding to the PRIP-1 binding site reduced the cell surface expression of γ2 subunit-containing GABAA receptors in cultured cell lines and neurons. These results suggest that PRIP is implicated in the trafficking of γ2 subunit-containing GABAA receptors to the cell surface, probably by acting as a bridging molecule between GABARAP and the receptors..
14. Takashi Kanematsu, Atsushi Yasunaga, Yoshito Mizoguchi, Akiko Kuratani, Josef T. Kittler, Jasmina N. Jovanovic, Kei Takenaka, Keiichi I. Nakayama, Kiyoko Fukami, Tadaomi Takenawa, Stephen J. Moss, Junichi Nabekura, Masato Hirata, Modulation of GABAA receptor phosphorylation and membrane trafficking by phospholipase C-related inactive protein/protein phosphatase 1 and 2A signaling complex underlying brain-derived neurotrophic factor-dependent regulation of GABAergic inhibition, Journal of Biological Chemistry, 10.1074/jbc.M603118200, 281, 31, 22180-22189, 2006.08, [URL], Brain-derived neurotrophic factor (BDNF) modulates several distinct aspects of synaptic transmission, including GABAergic transmission. Exposure to BDNF alters properties of GABAA receptors and induces changes in the expression level at the cell surface. Although phospholipase C-related inactive protein-1 (PRIP-1) plays an important role in GABAA receptor trafficking and function, its role in BDNF-dependent modulation of these receptors, together with the role of PRIP-2, was investigated using neurons cultured from PRIP double knock-out mice. The BDNF-dependent inhibition of whole cell GABA-evoked currents observed in wild type neurons was not detected in neurons cultured from knock-out mice. Instead, a gradual increase in GABA-evoked currents in these neurons correlated with a gradual increase in phosphorylation of GABAA receptor β3 subunit in response to BDNF. To characterize the specific role(s) that PRIP plays as components of underlying molecular machinery, we examined the recruitment of protein phosphatase(s) to GABAA receptors. We demonstrate that PRIP associates with phosphatases as well as with β subunits. PRIP was found to colocalize with GABAA receptor clusters in cultured neurons and with recombinant GABAA receptors when co-expressed in HEK293 cells. Importantly, a peptide mimicking a domain of PRIP involved in binding to β subunits disrupted the co-localization of these proteins in HEK293 cells and potently inhibited the BDNF-mediated attenuation of GABAA receptor currents in wild type neurons. Together, the results suggest that PRIP plays an important role in BDNF-dependent regulation of GABAA receptors by mediating the specific association between β subunits of these receptors with protein phosphatases..
15. Miho Terunuma, Il Sung Jang, Sang Hoon Ha, Josef T. Kittler, Takashi Kanematsu, Jasmina N. Jovanovic, Keiichi I. Nakayama, Norio Akaike, Sung Ho Ryu, Stephen J. Moss, Masato Hirata, GABAA receptor phospho-dependent modulation is regulated by phospholipase C-related inactive protein type 1, a novel protein phosphatase 1 anchoring protein, Journal of Neuroscience, 10.1523/JNEUROSCI.1323-04.2004, 24, 32, 7074-7084, 2004.08, [URL], GABAA receptors are critical in controlling neuronal activity. Here, we examined the role for phospholipase C-related inactive protein type 1 (PRIP-1), which binds and inactivates protein phosphatase 1α (PP1α) in facilitating GABAA receptor phospho-dependent regulation using PRIP-1-/- mice. In wild-type animals, robust phosphorylation and functional modulation of GABAA receptors containing β3 subunits by cAMP-dependent protein kinase was evident, which was diminished in PRIP-1-/- mice. PRIP-1-/- mice exhibited enhanced PP1α activity compared with controls. Furthermore, PRIP-1 was able to interact directly with GABAA receptor β subunits, and moreover, these proteins were found to be PP1α substrates. Finally, phosphorylation of PRIP-1 on threonine 94 facilitated the dissociation of PP1α-PRIP-1 complexes, providing a local mechanism for the activation of PP1α. Together, these results suggest an essential role for PRIP-1 in controlling GABAA receptor activity via regulating subunit phosphorylation and thereby the efficacy of neuronal inhibition mediated by these receptors..
16. Takashi Kanematsu, Il Sung Jang, Taku Yamaguchi, Hiroyasu Nagahama, Kenji Yoshimura, Kiyoshi Hidaka, Miho Matsuda, Hiroshi Takeuchi, Yoshio Misumi, Keiko Nakayama, Tsuneyuki Yamamoto, Norio Akaike, Masato Hirata, Keiichi Nakayama, Role of the PLC-related, catalytically inactive protein p130 in GABAA receptor function, EMBO Journal, 10.1093/emboj/21.5.1004, 21, 5, 1004-1011, 2002.03, [URL], The protein p130 was isolated from rat brain as an inositol 1, 4, 5-trisphosphate-binding protein with a domain organization similar to that of phospholipase C-δ1 but lacking PLC activity. We show that p130 plays an important role in signaling by the type A receptor for γ-aminobutyric acid (GABA). Yeast two-hybrid screening identified GABARAP (GABAA receptor-associated protein), which is proposed to contribute to the sorting, targeting or clustering of GABAA receptors, as a protein that interacts with p130. Furthermore, p130 competitively inhibited the binding of the γ2 subunit of the GABAA receptor to GABARAP in vitro. Electrophysiological analysis revealed that the modulation of GABA-induced Cl-current by Zn2+ or diazepam, both of which act at GABAA receptors containing γ subunits, is impaired in hippocampal neurons of p130 knockout mice. Moreover, behavioral analysis revealed that motor coordination was impaired and the intraperitoneal injection of diazepam induced markedly reduced sedative and antianxiety effects in the mutant mice. These results indicate that p130 is essential for the function of GABAA receptors, especially in response to the agents acting on a γ2 subunit..
17. Kenji Yoshimura, Hiroshi Takeuchi, Osamu Sato, Kiyoshi Hidaka, Naoko Doira, Miho Terunuma, Kae Harada, Yasuo Ogawa, Yushi Ito, Takashi Kanematsu, Masato Hirata, Interaction of p130 with, and Consequent Inhibition of, the Catalytic Subunit of Protein Phosphatase 1α, Journal of Biological Chemistry, 10.1074/jbc.M009677200, 276, 21, 17908-17913, 2001.01, [URL], The protein p130 was originally isolated from rat brain as an inositol 1,4,5-trisphosphate-binding protein with a domain organization similar to that of phospholipase C-δ1 but which lacks phospholipase C activity. Yeast two-hybrid screening of a human brain cDNA library for clones that encode proteins that interact with p130 has now led to the identification of the catalytic subunit of protein phosphatase 1α (PP1cα) as a p130-binding protein. The association between p130 and PP1cα was also confirmed in vitro by an overlay assay, a "pull-down" assay, and surface plasmon resonance analysis. The interaction of p130 with PP1cα resulted in inhibition of the catalytic activity of the latter in a p130 concentration-dependent manner. Immunoprecipitation and immunoblot analysis of COS-1 cells that stably express p130 and of mouse brain extract with antibodies to p130 and to PP1cα also detected the presence of a complex of p130 and PP1cα. The activity of glycogen phosphorylase, which is negatively regulated by dephosphorylation by PP1cα, was higher in COS-1 cells that stably express p130 than in control COS-1 cells. These results suggest that, in addition to its role in inositol 1,4,5-trisphosphate and Ca2+ signaling, p130 might also contribute to regulation of protein dephosphorylation through its interaction with PP1cα..
18. Takashi Kanematsu, Kenji Yoshimura, Kiyoshi Hidaka, Hiroshi Takeuchi, Matilda Katan, Masato Hirata, Domain organization of p130, PLC-related catalytically inactive protein, and structural basis for the lack of enzyme activity, European Journal of Biochemistry, 10.1046/j.1432-1327.2000.01291.x, 267, 9, 2731-2737, 2000.05, [URL], The 130-kDa protein (p130) was isolated as a novel inositol 1,4,5- trisphosphate [Ins(1,4,5)P3)-binding protein similar to phospholipase C-δ1 (PLC-δ1), but lacking catalytic activity [Kanematsu, T., Takeya, H., Watanabe, Y., Ozaki, S., Yoshida, M., Koga, T., Iwanaga, S. and Hirata, M. (1992) J. Biol. Chem. 267, 6518-6525, Kanematsu, T., Misumi, Y., Watanabe, Y., Ozaki, S., Koga, T., Iwanaga, S., Ikehara, Y. and Hirata, M. (1996) Biochem, J. 313, 319-3251. To test experimentally the domain organization of p130 and structural basis for lack of PLC activity, we subjected p130 to limited proteolysis and also constructed a number of chimeras with PLC-δ1. Trypsin treatment of p130 produced four major polypeptides with molecular misses of 86 kDa, 55 kDa, 33 kDa and 25 kDa. Two polypeptides of 86 kDa and 55 kDa started at Lys93 and were CalCulated to end at Arg851 and Arg568, respectively. Using the same approach, it has been found that the polypeptides of 33 kDa and 25 kDa are likely to correspond to regions between Val569 and Arg851 and Lys869 and Leu1096, respectively. All the proteolytic sites were in interconnecting regions between the predicted domains, therefore supporting domain organization based on sequence similarity to PLC- δ1 and demonstrating that all domains of p130, including the unique region at the C-terminus, are stable, tightly folded structures. p130 truncated at either or both the N-terminus (94 amino acids) and C-terminus (851-1096 amino acids) expressed in COS-1 cells showed no catalytic activity, indicating that p130 has intrinsically no PLC activity. A number of chimeric molecules between p130 and PLC-δ1 were constructed and assayed for PLC activity. It was shown that structural differences in interdomain interactions exist between the two proteins, as only some domains of p130 could replace the corresponding structures in PLC-δ1 to form a functional enzyme. These results suggest that p130 and the related proteins could represent a new protein family that may play some distinct role in cells due to the capability of binding Ins(1,4,5)P3 but the lack of catalytic activity..
19. Xin H.B., Rogers K., Qi Y., Kanematsu T. & Fleischer S., Three amino acid residues determine selective binding of FK506-binding protein 12.6 to the cardiac ryanodine., Journal of Biological Chemistry , 274, 15315~15319, 1999.01.
20. Hiroshi Takeuchi, Takashi Kanematsu, Yoshio Misumi, Hassan Bin Yaakob, Hitoshi Yagisawa, Yukio Ikehara, Yutaka Watanabe, Zheng Tan, Stephen B. Shears, Masato Hirata, Localization of a high-affinity inositol 1,4,5-trisphosphate/inositol 1,4,5,6-tetrakisphosphate binding domain to the pleckstrin homology module of a new 130 KDa protein
Characterization of the determinants of structural specificity, Biochemical Journal, 10.1042/bj3180561, 318, 2, 561-568, 1996.09, [URL], We have previously identified a novel 130 kDa protein (p130) which binds Ins(1,4,5)P3 and shares 38% sequence identity with phospholipase C-δ1 [Kanematsu, Misumi, Watanabe, Ozaki, Koga, Iwanaga, Ikehara and Hirata (1996) Biochem. J. 313, 319-325]. We have now transfected COS-1 cells with genes encoding the entire length of the molecule or one of several truncated mutants, in order to locate the region for binding of Ins(1,4,5)P3. Deletion of N-terminal residues 116-232, the region which corresponds to the pleckstrin homology (PH) domain of the molecule, completely abolished binding activity. This result was confirmed when the PH domain itself (residues 95-232), isolated from a bacterial expression system, was found to bind [3H]Ins(1,4,5)P3. We also found that Ins(1,4,5,6)P4 was as efficacious as Ins(1,4,5)P3 in displacing [3H]Ins(1,4,5)P3, suggesting that these two polyphosphates bind to p130 with similar affinity. This conclusion was confirmed by direct binding studies using [3H]Ins(1,4,5,6)P4 with high specific radioactivity which we prepared ourselves. Binding specificity was also examined with a variety of inositol phosphate derivatives. As is the case with other PH domains characterized to date, we found that the 4,5-vicinal phosphate pair was an essential determinant of ligand specificity. However, the PH domain of p130 exhibited some novel features. For example, the 3- and/or 6-phosphates could also contribute to overall binding; this contrasts with some other PH domains where these phosphate groups decrease ligand affinity by imposing a steric constraint. Secondly, a free monoester 1-phosphate substantially increased binding affinity, which is a situation so far unique to the PH domain of p130..
21. Takashi Kanematsu, Yoshio Misumi, Yutaka Watanabe, Shoichiro Ozaki, Toshitaka Koga, Sadaaki Iwanaga, Yukio Ikehara, Masato Hirata, A new inositol 1,4,5-trisphosphate binding protein similar to phospholipase C-δ1, Biochemical Journal, 10.1042/bj3130319, 313, 1, 319-325, 1996.01, [URL], We have reported that two inositol 1,4,5-trisphosphate binding proteins, with molecular masses of 85 and 130 kDa, were purified from rat brain; the former protein was found to be the δ1-isoenzyme of phospholipase C (PLC-δ1) and the latter was an unidentified novel protein [Kanematsu, Takeya, Watanabe, Ozaki, Yoshida, Koga, Iwanaga and Hirata (1992) J. Biol. Chem. 267, 6518-6525]. Here we describe the isolation of the full-length cDNA for the 130 kDa Ins(1,4,5)P3 binding protein, which encodes 1096 amino acids. The predicted sequence of the 130 kDa protein had 38.2% homology to that of PLC-δ1. Three known domains of PLC-δ1 (pleckstrin homology and putative catalytic X and Y domains) were located at residues 110-222, 377-544 and 585-804 with 35.2%, 48.2% and 45.8% homologies respectively. However, the protein showed no PLC activity to phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol. The 130 kDa protein expressed by transfection in COS-1 cells bound Ins(1,4,5)P3 in the same way as the molecule purified from brain. Thus the 130 kDa protein is a novel Ins(1,4,5)P3 binding protein homologous to PLC-δ1, but with no catalytic activity. The functional significance of the 130 kDa protein is discussed..
22. Masako Yoshida, Takashi Kanematsu, Yutaka Watanabe, Toshitaka Koga, Shoichiro Ozaki, Sadaaki Iwanaga, Masato Hirata, D-myo-inositol 1,4,5-trisphosphate-binding proteins in rat brain membranes, Journal of biochemistry, 10.1093/oxfordjournals.jbchem.a124447, 115, 5, 973-980, 1994.01, [URL], Rat brain membrane fractions obtained using Triton X-100 were applied to a D-myo-inositol 1,4,5-trisphosphate [D-Ins(1,4,5)P3] immobilized column, followed by gel filtration and anion-exchange chromatography. Two proteins with molecular masses of 130 and 85 kDa, as assessed by SDS-polyacrylamide gel electrophoresis, were purified to apparent homogeneity as D-[3H] Ins(1,4,5)P3-binding proteins with no D-Ins(1,4,5)P3-metabolizing activity. Partial amino acid sequence determinations of these proteins revealed that the 130 kDa protein appears to be a new D-Ins(1,4,5)P3-binding protein and the 85 kDa protein is δ1-isozyme of phospholipase C. We have previously purified 130 and 85 kDa proteins, as D-[3H]Ins(1, 4, 5)P3-binding proteins, from rat brain cytosol fraction. Antibodies against the 130 kDa protein from the cytosol cross-reacted with the membrane 130 kDa protein purified in this study, suggesting that the membrane 130 kDa protein is likely to be the same as the protein from the cytosol fraction. The inhibition of D-[3H]Ins(1,4,5)P3 binding by D-isomers of inositol phosphates available clarified that the 130 kDa protein has a similar affinity for D-Ins(1,4,5,6)P4 to that for D-Ins(1,4,5)P3, while the 85 kDa protein is specific to D-Ins(1,4,5)P3..
23. T. Kanematsu, H. Takeya, Y. Watanabe, S. Ozaki, M. Yoshida, T. Koga, S. Iwanaga, M. Hirata, Putative inositol 1,4,5-trisphosphate binding proteins in rat brain cytosol, Journal of Biological Chemistry, 267, 10, 6518-6525, 1992.01, In previous works, we synthesized a series of inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) analogs, with a substituent on the second carbon of the inositol ring. Using these analogs, the Ins(1,4,5)P3 affinity media were also synthesized (Hirata, M., Watanabe, Y., Ishimatsu, T., Yanaga, F., Koga, T., and Ozaki, S. (1990) Biochem. Biophys. Res. Commun. 168, 379-386). When the cytosol fraction from the rat brain was applied to an Ins(1,4,5)P3 affinity column, an eluate with a 2 M NaCl solution was found to have remarkable Ins(1,4,5)P3-binding activity. The active fraction was further fractionated with gel filtration chromatography, and two proteins with an apparent molecular mass of 130 or 85 kDa were found to be Ins(1,4,5)P3- binding proteins but with no Ins(1,4,5)P3 metabolizing activities. Partial amino acid sequences determined after proteolysis and reversed-phase chromatography revealed that the protein with an apparent molecular mass of 85 kDa is the δ-isozyme of phospholipase C and that of 130 kDa has no sequence the same as the Ins(1,4,5)P3-recognizing proteins hitherto examined. Ins(1,4,5)P3 at concentrations greater than 1 μM strongly inhibited 85-kDa phospholipase Cδ activity, without changing its dependence on the concentrations of free Ca2+ and H+. Among inositol phosphates examined, Ins(3,4,5,6)P4 inhibited the binding of [3H]Ins(1,4,5)P3 to the 130-kDa protein at much the same concentrations as seen with Ins(1,4,5)P3. This report seems to be the first evidence for the presence of soluble Ins(1,4,5)P3-binding proteins in the rat brain, one of which is the δ isozyme of phospholipase C..
主要総説, 論評, 解説, 書評, 報告書等
1. Kanematsu T., Mizokami A., Watanabe K., Hirata M., Regulation of GABA(A) receptor surface expression with special reference to the invilvement of GABARAP and PRIP. , J. Pharmacol. Sci., 2007.08.
2. Kanematsu T., Takeuchi H., Terunuma M., Hirata M., PRIP, a novel Ins(1,4,5)P3 binding protein, functional significance in Ca2+ signaling and extension to neuroscience and beond., Mol. Cells, 20: 305-314, 2005.01.
3. 兼松 隆、照沼美穂、後藤英文、倉谷顕子、平田雅人., GABA(A) 受容体の一生とそれを調節する分子達, 日本薬理学雑誌, 123: 105-112, 2004.01.
4. 兼松 隆., 多機能性分子PRIPと抑制性シナプス構築の分子メカニズム, 基礎歯科医学会雑誌, 第45巻、第3号 pp93-102, 2003.01.
5. 兼松 隆、平田雅人., GABAA受容体構築に関わる分子達, 生化学, 第75巻、第5号 pp378-382, 2003.01.
6. 兼松 隆、竹内 弘、吉村研治、平田雅人., 新しい情報伝達蛋白質ファミリーの機能, 生体の科学, 51(6), 608-613, 2000.01.
7. 兼松 隆、平田雅人., 新規 Ins(1,4,5)P3 結合蛋白質と GABAA 受容体シグナリング, 福岡医学雑誌, 91(7), 159-164, 2000.01.
主要学会発表等
学会活動
所属学会名
日本薬理学会
日本生化学会
歯科基礎医学会
日本分子生物学会
日本細胞生物学会
福岡医学会
西日本骨関節関連疾患懇話会
北米神経科学会
学協会役員等への就任
2020.07~2022.06, 一般社団法人 歯科基礎医学会, 理事.
2018.05~2020.06, 一般社団法人 歯科基礎医学会, 理事.
2016.05~2018.06, 公益社団法人 日本薬理学会, 日本薬理学会編集委員.
2010.04~2014.03, 公益社団法人 日本薬理学会, 評議員.
2012.04~2016.03, 一般社団法人 歯科基礎医学会, 理事.
2000.04~2018.03, 歯科基礎医学会, 評議員.
2001.04~2009.01, 西日本骨関節関連疾患懇話会, 幹事.
学会大会・会議・シンポジウム等における役割
2021.10.09~2021.10.11, 第63回歯科基礎医学会学術大会, 日韓シンポジウムオーガナイザー.
2019.10.12~2019.10.14, 第61回歯科基礎医学会学術大会, 日韓シンポジウムオーガナイザー.
2019.09.05~2019.09.05, 第1回JRSDOF, 座長.
2008.01~2008.01, The Joint Meeting of the 3rd Symposium on Oral Health Science and Craniofacial Morphogenesis and Tissue Regeneration, 座長(Chairmanship).
2007.07~2007.07, 第7回西日本骨・関節関連疾患懇話会, 座長(Chairmanship).
2007.07~2007.07, The 5th Korea-Japan Conference on Cellular Signaling for Young Scientists, 座長(Chairmanship).
2005.10~2005.10, タンパク質解析講座, 座長(Chairmanship).
2005.07~2005.07, The 4th Japan-Korea Conference on Cellular Signaling for Young Scientists, 司会(Moderator).
2005.07~2005.07, 第5回西日本骨・関節関連疾患懇話会, 座長(Chairmanship).
2004.07~2004.07, The 3rd Japan-Korea Conference on Cellular Signaling for Young Scientists, 座長(Chairmanship).
2003.07~2003.07.01, The 2nd Japan-Korea Conference on Cellular Signaling for Young Scientists, 司会(Moderator).
2003.07~2003.07, The Third International Symposium on the Study of Brain Function, 司会(Moderator).
2003.07~2003.07, 第3回 西日本骨・関節関連疾患懇話会, 座長(Chairmanship).
2002.07~2002.07.01, 第2回 西日本骨・関節関連疾患懇話会, 座長(Chairmanship).
2007.07~2007.07.01, 日韓若手会議, 会議実行委員.
2005.07~2005.07, 日韓若手会議, 会議実行委員.
2003.07~2003.07, 日韓若手会議, 会議実行委員.
学会誌・雑誌・著書の編集への参加状況
2020.04~2021.03, 現代歯科薬理学 第6版, 国内, 編集委員.
2021.04~2023.03, 第3版 ポイントがよくわかる シンプル歯科薬理学, 国内, 編集委員.
2019.06~2021.12, 第2版 ポイントがよくわかる シンプル歯科薬理学, 国内, 編集委員.
2017.04~2021.12, 現代歯科薬理学 第6版, 国内, 編集委員.
2016.05~2020.05, Journal of Pharmacological Sciences, 国際, 編集委員.
学術論文等の審査
年度 外国語雑誌査読論文数 日本語雑誌査読論文数 国際会議録査読論文数 国内会議録査読論文数 合計
2020年度      
2019年度      
2008年度      
その他の研究活動
海外渡航状況, 海外での教育研究歴
Keystone Symposia (Islet and beta cell biology), UnitedStatesofAmerica, 2008.04~2008.04.
The 5th Korea-Japan Conference on Cellular Signaling for Young Scientists, Korea, 2007.07~2007.07.
第5回アジア・太平洋細胞生物学会, China, 2006.10~2006.11.
Keystone Symposia (Islet and beta cell biology), UnitedStatesofAmerica, 2006.02~2006.03.
第20回国際神経科学会, Austria, 2005.08~2005.08.
The 3rd Korea-Japan Conference on Cellular Signaling for Young Scientists, Korea, 2004.07~2004.07.
University College London, UnitedKingdom, 2003.04~2003.06.
University College London, UnitedKingdom, 2002.11~2003.01.
Pohang University of Science and Technology, Korea, 2002.07~2002.07.
外国人研究者等の受入れ状況
2007.12~2007.12, 2週間未満, Pusan National University School of Medicine, Korea, 日本学術振興会.
2007.12~2007.12, 2週間未満, Pusan National University School of Medicine, Korea, 日本学術振興会.
2007.03~2007.03, 2週間未満, University college London, UnitedKingdom, 日本学術振興会.
受賞
第18回歯科基礎医学会ライオン学術賞, 歯科基礎医学会, 2018.09.
第14回 歯科基礎医学会賞, 歯科基礎医学会, 2002.10.
The Distinguished Poster Award, The International Symposium on the Study of Brain Function, 2002.05.
研究資金
科学研究費補助金の採択状況(文部科学省、日本学術振興会)
2021年度~2023年度, 基盤研究(C), 代表, 抗腫瘍免疫を賦活化する新しい制癌シグナル分子の機能解明研究.
2018年度~2021年度, 基盤研究(C), 分担, 側坐核のドパミン神経刺激による下行性鎮痛系の増強を応用した新しい全身麻酔法の開発.
2017年度~2019年度, 基盤研究(C), 分担, 歯周病による中枢機能障害の基盤となるストレス応答性亢進機構の解明研究.
2017年度~2019年度, 基盤研究(C), 分担, PRIPの新奇癌細胞制御機構に着目した抗腫瘍薬開発研究.
2016年度~2018年度, 基盤研究(C), 代表, 膜リン脂質代謝変調がもたらす癌増悪メカニズムの解明研究.
2014年度~2015年度, 挑戦的研究(萌芽), 代表, 脂肪細胞の分化と脱分化制御の分子基盤解明研究.
2009年度~2011年度, 基盤研究(B), 代表, GABAシグナリング調節分子による摂食調節メカニズムの解明研究.
2009年度~2010年度, 挑戦的研究(萌芽), 代表, GABAA受容体輸送調節分子による神経因性疼痛制御の基礎的研究.
2010年度~2012年度, 基盤研究(B), 分担, 難治性がん性疼痛緩和のための痛みの病態生理に立脚した新たな治療法の開発.
2012年度~2014年度, 基盤研究(C), 分担, 新規細胞内輸送調節分子を介した疼痛制御機構の解明.
2015年度~2017年度, 基盤研究(C), 分担, 下行性鎮痛系の増強を応用した新しい全身麻酔法の開発:5-HT受容体リガンドの活用.
2015年度~2017年度, 基盤研究(C), 分担, オートファジーを介した黄色ブドウ球菌排除の分子基盤解明.
2007年度~2008年度, 萌芽研究, 代表, 新規分子とオートファジィーの関係を探る。−GABA(A)受容体の分子制御−.
2006年度~2009年度, 基盤研究(B), 分担, ヒト認知機能を障害させる遺伝子異常を持つモデル動物の作出とその病態解析.
2006年度~2008年度, 基盤研究(B), 代表, 肥満やインスリン分泌異常を引き起こす新規分子の役割解明研究.
2004年度~2008年度, 基盤研究(S), 分担, 新しい情報伝達タンパク質研究から迫る咬合と脳機能の関連
−基礎歯科学から先駆的情報発信−.
2003年度~2004年度, 基盤研究(C), 代表, GABA(A)受容体構築の分子メカニズム解明.
2000年度~2001年度, 奨励研究(A), 代表, GABA(A)受容体に対する新規Ins(1,4,5)
P3結合蛋白質の役割解明.
2000年度~2001年度, 特定領域研究(A)特定領域研究(B), 代表, 新規Ins(1,4,5)P3結合蛋白質はGABA(A)受容体の機能を修飾するか.
1997年度~1998年度, 奨励研究(A), 代表, 新規イノシトール1,4,5-三リン酸結合蛋白質の変異マウスの作製.
日本学術振興会への採択状況(科学研究費補助金以外)
2010年度~2013年度, 最先端・次世代研究開発支援プログラム, 代表, エネルギー代謝機構や摂食調節機構に関わる新規分子の機能解明研究.
2008年度~2008年度, 国際学会等派遣事業, 代表, Action of PRIP, an Ins(1,4,5)P3 binding protein, in insulin secretion.
2005年度~2005年度, 国際学会等派遣事業, 代表, PRIP分子はBDNF刺激によっておこるGABA(A)受容体の膜発現量減少に関わる..
2003年度~2004年度, 二国間交流, 分担, GABAシグナリングに関わる新しい分子の役割.
2002年度~2003年度, 平成14年度海外研究開発動向調査, 代表, 新しい概念に基づいた抗不安薬/抗けいれん薬の研究開発動向の調査.
競争的資金(受託研究を含む)の採択状況
2008年度~2009年度, 日本糖尿病財団, 代表, インスリン開口放出を制御する新奇分子の役割解明研究.
2007年度~2008年度, 金原一郎記念医学医療振興財団, 代表, 開口分泌を調節する新奇分子の機能解明.
2007年度~2008年度, ブレインサイエンス振興財団, 代表, 新規分子によるGABA(A)受容体の輸送調節.
2006年度~2006年度, 武田科学振興財団一般研究奨励, 代表, 過食と肥満に関わる新規分子の基礎的研究.
2005年度~2005年度, 第37回(2005年度)内藤記念科学奨励金(研究助成), 代表, 新規分子(PRIP)によるGABA(A)受容体膜発現調節機構の分子メカニズム解明研究.
2004年度~2004年度, 第16回加藤記念研究助成, 代表, 新規情報伝達タンパク質(PRIP)の機能解析.
2003年度~2003年度, 持田記念研究助成, 代表, 新規Ins(1,4,5)P3結合性タンパク質PRIPの心臓・血管機能への関わり.
2002年度~2002年度, 武田科学振興財団医学系研究奨励, 代表, PRIP-1分子はGABA(A)受容体の品質管理に関わるか.
2001年度~2001年度, 平成13年度 稲盛財団研究助成金, 代表, 抑制性シナプス情報伝達の分子機構の解明に関する研究.
2000年度~2000年度, 平成12年度 興和生命科学振興財団研究助成金, 代表, GABA受容体構築における新しい分子の意外な関わり.
1998年度~1998年度, 平成10年度 上原記念生命科学財団研究奨励金, 代表, ノックアウトマウス・培養細胞を用いた、新規イノシトール1,4,5-三リン酸結合蛋白質(p130)の生理機能解明に関する研究.
1992年度~1992年度, 加藤記念バイオサイエンス研究振興財団(海外派遣助成金), 代表, 新規イノシトール三リン酸結合タンパク質の精製.
共同研究、受託研究(競争的資金を除く)の受入状況
2008.04~2009.03, 代表, 2光子顕微鏡をによる新奇分子を介した開口放出制御の解明研究.
2008.04~2009.03, 分担, GABA(A)受容体の膜発現調節の分子機構解明研究.
2007.04~2008.03, 分担, GABAシグナリングにおける新規分子PRIPの役割解明.
2006.04~2007.03, 分担, GABAシグナリングにおける新規分子PRIPの役割解明.
2005.04~2006.03, 分担, GABAシグナリングにおける新規分子PRIPの役割解明.
学内資金・基金等への採択状況
2004年度~2006年度, 4-2-4アクションプラン(若手研究リーダー), 代表, 新規分子の機能解明研究.

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pure2017年10月2日から、「九州大学研究者情報」を補完するデータベースとして、Elsevier社の「Pure」による研究業績の公開を開始しました。
 
 
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