The cholesterol metabolism of neuroendocrine cells and crosstalk of the hormone secretion

• Project/Area Number: 22570133
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Akita Prefectural University (2011-2012); Gunma University (2010)
• Principal Investigator: HOSAKA Masahiro 秋田県立大学, 生物資源科学部, 教授 (80311603)
• Co-Investigator(Renkei-kenkyūsha): WATANABE Tsuyoshi 旭川医科大学, 医学部, 教授 (80220903) ; YAMADA Keiichi 群馬大学, 工学研究科, 助教 (70323334)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2010: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ホルモンと生理活性物質 / 内分泌細胞 / 分泌顆粒 / グラニンタンパク質 / セクレトグラニンIII / コレステロール / ペプチドホルモン / 膜脂質組成 / ホルモン分泌

Research Abstract

Prior to secretion, regulated peptide hormones are selectively sorted to secretory granules (SGs) at the trans-Golgi network (TGN) in endocrine cells. Secretogranin III (SgIII) appears to facilitate SG sorting process by tethering of protein aggregates containing chromogranin A (CgA) and peptide hormones to the cholesterol-rich SG membrane (SGM). Here, we evaluated the role of SgIII in SG sorting in AtT-20 cells transfected with small interfering RNA targeting SgIII. In the SgIII-knockdown cells, the intracellular retention of CgA was greatly impaired, and only a trace amount of CgA was localized within the vacuoles formed in the TGN, confirming the significance of SgIII in both the tethering of CgA-containing aggregates and the establishment of the proper SG morphology. Although the intracellular retention of proopiomelanocortin (POMC) was considerably impaired in SgIII-knockdown cells, residual ACTH/POMC was still localized to some few remaining SGs together with another granin protein, secretogranin II (SgII), and was secreted in a regulated manner. Biochemical analyses indicated that SgII bound directly to the SGM in a cholesterol-dependent manner and was able to retain the aggregated form of POMC, revealing a latent redundancy in the SG sorting and retention mechanisms, that ensures the regulated secretion of bioactive peptides.

Research Products

• [Journal Article] Chronic exercise enhances insulin secretion ability of pancreatic islets without change in insulin content in non-diabetic rats (2013)
  • Author(s): Tsuchiya, M., Manabe Y., Yamada, K., Furuichi, Y., Hosaka, M., Fujii, N.
  • Journal Title: BBRC Volume: 430 Pages: 676-682
• [Journal Article] Multiple sorting systems for secretory granules ensure the regulated secretion of peotide hormones (2013)
  • Author(s): Sun, M., Watanabe, T., Bochimoto, H., Sakai, Y., Torii, S., Takeuchi, T., Hosaka, M.
  • Journal Title: Traffic Volume: 14 Pages: 205-218
• [Journal Article] Multiple sorting systems for secretory granules ensure the regulated secretion of peptide hormones. (2013)
  • Author(s): Sun M
  • Journal Title: Traffic Volume: 14 Issue: 2 Pages: 205-218
  • DOI: 10.1111/tra.12029
  • Peer Reviewed
• [Journal Article] Chronic exercise enhances insulin secretion ability of pancreatic islets without change in insulin content in non-diabetic rats. (2013)
  • Author(s): Tsuchiya M, Manabe Y, Yamada K, Furuichi Y, Hosaka M, Fujii NL.
  • Journal Title: Biochem Biophys Res Commun Volume: 11 Issue: 2 Pages: 676-682
  • DOI: 10.1016/j.bbrc.2012.11.092
  • Peer Reviewed
• [Journal Article] A unique ball-shapeed Golgi apparatus in the rat pituitary ganadotrope: its functional implications in relation to the arrangement of microtuble network (2012)
  • Author(s): Watanabe, T., Sakai, Y., Koga, D., Bochimoto, H., Hira, Y., Hosaka, M., Ushiki, T.
  • Journal Title: J. Histochem. Cytochem Volume: 60 Pages: 588-602
• [Journal Article] Ratiometric Molecular Sensor for Monitoring Oxygen Levels in Living Cells (2012)
  • Author(s): Yoshihara, T., Yamaguchi, Y., Hosaka, M., Takeuchi, T., Tobita, S.
  • Journal Title: Angew Chem Int Ed Engl Volume: 51 Pages: 4418-4151
• [Journal Article] A unique ball-shaped Golgi apparatus in the rat pituitary gonadotrope: its functional implications in relation to the arrangement of the microtubule network. (2012)
  • Author(s): Watanabe T, Sakai Y, Koga D, Bochimoto H, Hira Y, Hosaka M, Ushiki T.
  • Journal Title: J Histochem Cytochem. Volume: 60 Issue: 8 Pages: 588-602
  • DOI: 10.1369/0022155412448791
  • NAID: 120006522770
  • Peer Reviewed
• [Journal Article] Silylation Enhancement of Photodynamic Activity of Tetraphenylporphyrin Derivative (2011)
  • Author(s): Horiuchi, H., Kameya, T., Hosaka, M., Yoshimura, K., Kyushin, S., Matsumoto, H., Okutsu, T., Takeuchi, T., Hiratsuka, H.
  • Journal Title: J. Photochem. Photobiol Volume: 221 Pages: 98-104
• [Journal Article] Cyclophilin C-associated protein regulation of phagocytic functions via NFAT activation in macrophages (2011)
  • Author(s): Yamaguchi, R., Hosaka, M., Torii, S., Hou, N., Saito, N., Yoshimoto, Y., Imai., H., Takeuchi, T.
  • Journal Title: Brain Res Volume: 1397 Pages: 55-65
• [Journal Article] Luminal Interaction of Phogrin with Carboxypeptidase E for Effective Targeting to Secretory Granules (2011)
  • Author(s): Saito, N., Takeuchi, T., Kawano, A., Hosaka, M., Hou, N., Torii, S.
  • Journal Title: Traffic Volume: 12 Pages: 499-506
• [Journal Article] Silylation Enhancement of Photodynamic Activity of Tetraphenylporphyrin Derivative.J.Photochem.Photobiol. (2011)
  • Author(s): Horiuchi, H., Kameya, T., Hosaka, M., Yoshimura, K., Kyushin, S., Matsumoto, H., Okutsu, T., Takeuchi, T., Hiratsuka, H.
  • Journal Title: J.Photochem.Photobiol. Volume: 221 Issue: 1 Pages: 98-104
  • DOI: 10.1016/j.jphotochem.2011.04.032
  • Peer Reviewed
• [Journal Article] (The first two authors contributed equally to this work.): Cholesterol Biosynthesis Pathway Intermediates and Inhibitors Regulate Glucose-stimulated Insulin Secretion and Secretory Granule Formation in Pancreatic beta-Cells (2010)
  • Author(s): Tsuchiya, M., Hosaka, M., Moriguchi, T., Zhang, S., Suda, M., Yokota-Hashimoto, H., Shinozuka, K., Takeuchi, T
  • Journal Title: Endocrinology Volume: 151 Pages: 4705-4716
• [Journal Article] (The first three authors contributed equally to this work.): Phosphorescent Light-emitting Iridium Complexes Serve as a Hypoxia-sensing Probe for Tumor Imaging in Living Animals (2010)
  • Author(s): Zhang, S., Hosaka, M., Yoshihara, T., Negishi, K., Iida, Y., Tobita, S., Takeuchi, T.
  • Journal Title: Cancer Research Volume: 70 Pages: 4490-4498
• [Journal Article] Secretogranin III: a bridge between core hormone aggregates and the secretory granule membrane (2010)
  • Author(s): Hosaka M, Watanabe T
  • Journal Title: Endocrine J Volume: 57 Pages: 275-286
  • NAID: 10029584142
• [Journal Article] Cholesterol Biosynthesis Pathway Intermediates and Inhibitors Regulate Glucose-stimulated Insulin Secretion and Secretory Granule Formation in Pancreatic beta-Cells. (2010)
  • Author(s): Tsuchiya, M., Hosaka, M., Moriguchi, T., Zhang, S., Suda, M., Yokota-Hashimoto, H., Shinozuka, K., Takeuchi, T
  • Journal Title: Endocrinology Volume: 151 Pages: 4705-4716
  • Peer Reviewed
• [Journal Article] Phosphorescent Light-emtting lridium Complexes Serve as a Hypoxia-sensing Probe for Tumor lmaging in Living Animals. (2010)
  • Author(s): Zhang, S., Hosaka, M., Yoshihara, T., Negishi, K., lida, Y., Tobita, S., Takeuchi, T
  • Journal Title: Cancer Research Volume: 70 Pages: 4490-4498
  • Peer Reviewed
• [Journal Article] Secretogranin lll : a bridge between core homone aggregates and the secretory granule membrane. (2010)
  • Author(s): Hosaka M, Watanabe T
  • Journal Title: Endocrine J Volume: 57 Pages: 275-286
  • Peer Reviewed
• [Journal Article] A unique ball-shapeed Golgi apparatus in the rat pituitary ganadotrope : its functional implications in relation to the arrangement of microtuble network
  • Author(s): Watanabe, T., Sakai, Y., Koga, D., Bochimoto, H., Hira, Y., Hosaka, M., Ushiki, T.
  • Journal Title: J.Histochem.Cytochem. Volume: (In press)
  • Peer Reviewed
• [Journal Article] Luminal Interaction of Phogrin with Carboxypeptidase E for Effective Taraetina to Secretory Granules.
  • Author(s): Saito, N., Takeuchi, T., Kawano, A., Hosaka, M, Hou, N., Torii, S
  • Journal Title: Traffic Volume: Inpress
  • Peer Reviewed
• [Presentation] 様々な分泌刺激に対する細胞内膜系小器官の応答の解析:下垂体前葉性腺刺激ホルモン産生細胞をモデルとして (2012)
  • Author(s): 暮地本宙己、甲賀大輔、穂坂正博、牛木辰男、渡部剛
  • Organizer: 第117回日本解剖学会総会
  • Place of Presentation: 甲府市
  • Year and Date: 2012-03-26
• [Presentation] 内分泌細胞の分泌顆粒形成におけるグラニンタンパク質の役割 (2012)
  • Author(s): 穂坂 正博, 孫夢, 鳥居征司, 竹内利行, 暮地本宙己, 渡部剛
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡
• [Presentation] イリジウム錯体で低酸素病態をイメージングする (2012)
  • Author(s): 寺田幹、吉原利忠、飛田成史、穂坂正博
  • Organizer: 第21回秋田応用生命科学研究会
  • Place of Presentation: 秋田
• [Presentation] 内分泌細胞の分泌顆粒形成におけるグラニンタンパク質の役割 (2012)
  • Author(s): 穂坂正博、孫夢、暮地本宙己、渡部剛
  • Organizer: 第20回秋田応用生命科学研究会
  • Place of Presentation: 秋田
• [Presentation] 低酸素病態イメージングプローブの開発:イリジウム錯体による腫瘍のイメージング (2012)
  • Author(s): 穂坂正博、寺田幹、吉原利忠、竹内利行、飛田成史
  • Organizer: 第78回日本生化学会東北支部例会
  • Place of Presentation: 山形
• [Presentation] 様々な分泌刺激に対する細胞内膜系小器官の応答の解析:下垂体前葉性腺刺激ホルモン産生細胞をモデルとして (2012)
  • Author(s): 暮地本宙己、甲賀大輔、穂坂正博、牛木辰男、渡部剛
  • Organizer: 第117回日本解剖学会総会
  • Place of Presentation: 甲府
• [Presentation] Iridiumcomplex probes for monitoring of cellular oxygen levels and imaging of hypoxic tissues (2012)
  • Author(s): Tobita, S., Yoshihara, T., Kobayashi, A., Ichikawa, K., Hosaka, M., Takeuchi, T
  • Organizer: SPIE
  • Place of Presentation: San Francisco
• [Presentation] 内分泌細胞の分泌顆粒形成におけるグラニンタンパク質の役割 (2012)
  • Author(s): 穂坂 正博, 孫夢, 鳥居征司, 竹内利行, 暮地本宙己, 渡部剛
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡市
• [Presentation] Iridiumcomplex probes for monitoring of cellular oxygen levels and imaging of hypoxictissues (2012)
  • Author(s): Tobita, S., Yoshihara, T., Kobayashi, A., Ichikawa, K., Hosaka, M., Takeuchi,T
  • Organizer: SPIE
  • Place of Presentation: San Francisco, USA
• [Presentation] 神経内分泌細胞の分泌顆粒形成機序 (2011)
  • Author(s): 穂坂正博
  • Organizer: 第18回秋田応用生命科学研究会
  • Place of Presentation: 秋田市
  • Year and Date: 2011-05-27
• [Presentation] 神経内分泌細胞の分泌顆粒形成機序 (2011)
  • Author(s): 穂坂正博
  • Organizer: 第18回秋田応用生命科学研究会
  • Place of Presentation: 秋田
• [Presentation] Iridium complex, a phosphorescent light-emitting diode material, serves as a novel chemical probe for imaging hypoxic tumor tissues (2010)
  • Author(s): Masahiro Hosaka
  • Organizer: 2010 World Molecular Imaging Congress
  • Place of Presentation: Kyoto
  • Year and Date: 2010-09-11
• [Presentation] lridium complex, a phosphorescent light-emitting diode material, serves as a novel chemical probe for imaging hypoxic tumor tissues (2010)
  • Author(s): Masahiro Hosaka
  • Organizer: 2010 World Molecular lmaging Congress
  • Place of Presentation: 京都
  • Year and Date: 2010-09-11
• [Presentation] イリジウム錯体で低酸素病態をイメージングする
  • Author(s): 寺田幹、吉原利忠、飛田成史、穂坂正博
  • Organizer: 第21回秋田応用生命科学研究会
  • Place of Presentation: 秋田市
• [Presentation] 内分泌細胞の分泌顆粒形成におけるグラニンタンパク質の役割
  • Author(s): 穂坂正博、孫夢、暮地本宙己、渡部剛
  • Organizer: 第20回秋田応用生命科学研究会
  • Place of Presentation: 秋田市
• [Presentation] 低酸素病態イメージングプローブの開発：イリジウム錯体による腫瘍のイメージング
  • Author(s): 穂坂正博、寺田幹、吉原利忠、竹内利行、飛田成史
  • Organizer: 第78回日本生化学会東北支部例会
  • Place of Presentation: 山形市
• [Book] 疾患克服をめざしたケミカルバイオロジー; りん光プローブの設計・開発に基づくin vivo低酸素環境イメージング (2012)
  • Author(s): 飛田成史、吉原利忠、穂坂正博、竹内利行
  • Publisher: 実験医学増刊
• [Book] 第一線の科学者が語る 生活習慣病研究の最前線―メタボ・老化・がん研究からiPS細胞まで (2012)
  • Author(s): 北村忠弘、北川浩史、 穂坂正博、小島至 著
  • Total Pages: 69
  • Publisher: 上毛新聞社
• [Book] 実験医学増刊Vol.30 No.7 (2012)
  • Author(s): 飛田成史、吉原利忠、穂坂正博、竹内利行
  • Total Pages: 226
  • Publisher: 羊土社
• [Book] 第一線の科学者が語る 生活習慣病研究の最前線-メタボ・老化・がん研究から iPS細胞まで
  • Author(s): 北村忠弘、北川浩史、穂坂正博、小島至著
  • Publisher: 上毛新聞社
• [Remarks] 研究室開設ホームページ
  • URL: http://www.akita-pu.ac.jp/bioresource/dbt/molb/mhosaka/index.html
• [Remarks] 大学運営研究者総覧
  • URL: http://www.akita-pu.ac.jp/stic/souran/scholar/detail.php?id=270
• [Remarks] 秋田県立大学 生物資源科学部 応用生物科学科 分子細胞機能研究グループ 穂坂研究室
  • URL: http://www.akita-pu.ac.jp/bioresource/dbt/molb/mhosaka/index.html
• [Remarks] 秋田県立大学 地域連携・研究推進センターHOME＞研究者総覧
  • URL: http://www.akita-pu.ac.jp/stic/souran/scholar/detail.php?id=270
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  • URL: http://www.akita-pu.ac.jp/bioresource/dbt/molb/mhosaka/index.html
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  • URL: http://www.akita-pu.ac.jp/stic/souran/scholar/detail.php?id=270
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  • URL: http://www.imcr.gunma-u.ac.jp/lab/secbio/page5/page5.html
• [Patent(Industrial Property Rights)] 含ケイ素置換基を導入した化合物、並びにそれを含む一重項酸素発生剤及び癌治療薬 (2013)
  • Inventor(s): 堀内宏明、穂坂正博、平塚浩士、竹内利行、久新荘一郎、石田真太郎
  • Industrial Property Rights Holder: 国立大学法人群馬大学
  • Industrial Property Number: 2012-531819
  • Filing Date: 2013-02-05
• [Patent(Industrial Property Rights)] 新規蛍光化合物およびそれを用いた細胞内コレステロールの検出方法 (2013)
  • Inventor(s): 吉原利忠、飛田成史、竹内利行、穂坂正博
  • Industrial Property Rights Holder: 国立大学法人群馬大学
  • Filing Date: 2013-03-29
• [Patent(Industrial Property Rights)] 含ケイ素蛍光化合物および該化合物を用いた蛍光標識剤 (2012)
  • Inventor(s): 篠塚和夫、森口朋尚、竹内利行、穂坂正博
  • Industrial Property Rights Holder: 国立大学法人群馬大学
  • Filing Date: 2012-03-16
• [Patent(Industrial Property Rights)] 新規化合物およびそれを含む機能性プローブNovel compound and functional luminescent probe comprising same (2010)
  • Inventor(s): 飛田成史, 吉原利忠, 穂坂正博, 竹内利行
  • Industrial Property Rights Holder: 国立大学法人群馬大学
  • Filing Date: 2010-04-22
  • Overseas
• [Patent(Industrial Property Rights)] 新規化合物およびそれを含む機能性発光プローブ (2009)
  • Inventor(s): 飛田成史,吉原利忠,穂坂正博,竹内利行
  • Industrial Property Rights Holder: 国立大学法人群馬大学
  • Industrial Property Number: 2010-533937
  • Filing Date: 2009-10-16
• [Patent(Industrial Property Rights)] Novel Compound and Functional Luminescent Probe Comprising the Same (新規化合物およびそれを含む機能性発光プローブ) (2009)
  • Inventor(s): 飛田成史,吉原利忠,穂坂正博,竹内利行
  • Industrial Property Rights Holder: 国立大学法人群馬大学
  • Filing Date: 2009-10-16
  • Overseas
• [Patent(Industrial Property Rights)] Novel Compound and Functional Luminescent Probe Comprising the Same (新規化合物およびそれを含む機能性発光プローブ) (2009)
  • Inventor(s): 飛田成史,吉原利忠,穂坂正博,竹内利行
  • Industrial Property Rights Holder: 国立大学法人群馬大学
  • Filing Date: 2009-10-16
  • Overseas