Bimodal Regulation of Plasmalemmal Ca2+ entry by the coupling of mitochondria and the endoplasmic reticulum

• Project/Area Number: 18590211
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General physiology
• Research Institution: Nagoya University of Arts and Sciences
• Principal Investigator: KUBA Kenji Nagoya University of Arts and Sciences, Faculty of Nutritional Sciences, Professor (60080561)
• Co-Investigator(Kenkyū-buntansha): KUBA Masako Nagoya University of Arts and Sciences, Faculty of Nutritional Sciences, Associate Professor (90351212) ; HIGURE Yoko Nagoya University of Arts and Sciences, Faculty of Nutritional Sciences, Assistant Professor (30325633)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,800,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥300,000); Fiscal Year 2007: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2006: ¥2,500,000 (Direct Cost: ¥2,500,000)
• Keywords: Brown adipocyte / Mitochondria / endoplasmic reticulum / Ca^<2+> release / Capacitative Ca^<2+> entry / β3receptor / α1 receptor / energy balance / α1受容体 / カルシウムイオン / 脱共役 / Ca^<2+>誘起性Ca^<2+>遊離 / ノルアドレナリン

Research Abstract

Obesity is the result of excess energy intake and/or decreased energy consumption. Energy is consumed by basal metabolic activity, muscle activity and thermogenesis. Adrenergic activations of lipolysis and uncoupling proteins in brown adipocytes lead to heat production without oxidative phosphorylation. The energy dissipated by this process is the H^+ electrochemical potential across the mitochondrial membrane generated by H^+ pumps, electron transfer chains, that require NADH and FADH2 produced by Ca^<2+>-dependent dehydrogeneses in TCA cycle. Thus, this process is strongly affected by the level of intracellular free Ca^<2+> ([Ca^<2+>]i), which are regulated by Ca^<2+> binding, Ca^<2+> entry and extrusion at the plasma membrane, Ca^<2+> release and uptake into, and from, mitochondria and the endoplasmic reticulum(ER). We studied how these organelles and the plasmalemma communicate with each other in regulating [Ca^<2+>]I and how these coupling are involved in thermogenesis in rat brown adipocytes. Our observations revealed new mechanisms of [Ca^<2+>]I, regulation in brown adipocytes:(1) uncoupling of oxidative phosphorylation activates a metabolite dependent Ca^<2+> entry at the plasmalemma, (2) mitochondrial Ca^<2+> release induces Ca^<2+> release from the ER, (3) Ca^<2+> depletion in the ER via mitochondria-induced Ca^<2+> release activates store-operated Ca^<2+> entry (SOC) in a fraction of cells and (4) Ca^<2+> depletion in the ER activates Ca^<2+> release from mitochondria. (5) These mechanisms are activated by the α- and fl-actions of noradrenaline, suggesting important roles in thermogenesis.

Research Products

• [Journal Article] Bidirectional Ca^<2+>-coupling of mitochondria with the endoplasmic reticulum and regulation of multimodal Ca^<2+> entries in rat brown adipocytes (2007)
  • Author(s): Kuba, M., Higure, Y., Susaki, H., Hayato, R. and Kuba, K.
  • Journal Title: Amer.J.Physiol. 292
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Enhancement of Ca^<2+>-induced Ca^<2+> release by cyclic ADP-ribose in frog motor nerve terminals (2007)
  • Author(s): Hachisuka, J., Soga-Sakakibara, S., Kubota, M., Narita, K. Kuba, K.
  • Journal Title: Neuroscience 146 Pages: 123-131
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Overexpression of human CD38/ADP-ribosyl cyclase enhances acetyl choline-induced Ca^<2+> signalling in rodent NG108-15 neuroblastoma cells (2007)
  • Author(s): Higashida, H., Bowden, S.E.H., Yokoyama, S. Salmina, A., Hashii, M., Hoshi, N., Zhang, J.-S., Knyjnik, R., Noda, M., Zhong, Z.G., Jin, D., Higashida, K., Takeda, H., Akita, T., Kuba, K., Yamagishi, S., Shimizu, N., Takasawa, S., Okamoto, H. and Robbins, J.
  • Journal Title: Neurosci Res. 57 Pages: 339-346
  • NAID: 10024413034
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Functional Ca^<2+>-coupling among mitochondrion,endoplasmic reticulum and plasmalemma in thermogenic brown adipocytes:Possible roles in energy consumption (2007)
  • Author(s): Kuba, M., Higure, Y., Hayato, R., Susaki, H.and Kuba, K.
  • Journal Title: Annual Report of Institute of Health and Nutrition, Nagoya University of Arts and Sciences 1 Pages: 41-54
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Bidirectional Ca^<2+>-coupling of mitochondria with the endoplasmic reticulum and regulation of multimodal Ca^<2+> entries in rat brown adipocytes. (2007)
  • Author(s): Kuba, M., Higure, Y., Susaki, H., Hayato, R. Kuba, K.
  • Journal Title: Amer. J. Physiol. 292
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Overexpression of human CD38/ADP-ribosyl cyclase enhances acetylcholine-induced Ca^<2+> signalling in rodent NG108-15 neuroblastoma cells. (2007)
  • Author(s): Higashida, H., Bowden, S. E. H., Yokoyama, S. Salmina, A., Hashii, M., Hoshi, N., Zhang, J.-S., Knyjnik, R., Noda, M., Zhong, Z. G., Jin, D., Higashida, K., Takeda, H., Akita, T., Kuba, K., Yamagishi, S., Shimizu, N., Takasawa, S., Okamoto, H., Robbins, J.
  • Journal Title: Neurosci Res. 57 Pages: 339-346
  • NAID: 10024413034
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] (2007) Enhancement of Ca^<2+>-induced Ca^<2+> release by cyclic ADP-ribose in frog motor nerve terminals. (2007)
  • Author(s): Hachisuka, J., Soga-Sakakibara, S., Kubota, M., Narita, K. Kuba, K.
  • Journal Title: Neuroscience. 146 Pages: 123-131
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Functional Ca^<2+>-coupling among mitochondrion, endoplasmic reticulum and plasmalemma in thermogenic brown adipocytes : Possible roles in energy consumption. (2007)
  • Author(s): Kuba, M., Higure, Y., Hayato, R., Susaki, H., Kuba, K.
  • Journal Title: Annual Report of Institute of Health and Nutrition, Nagoya University of Arts and Sciences. 1 Pages: 41-54
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Enhancement of Ca^<2+>-induced Ca<2+> release by cyclic ADP-ribose in frog motor nerve terminals. (2007)
  • Author(s): Hachisuka, J., Soga-Sakakibara, S., Kubota, M., Narita, K. Kuba, K.
  • Journal Title: Neuroscience 146 Pages: 123-131
  • Peer Reviewed
• [Journal Article] Overexpression of human CD38/ADP-ribosyl cyclase enhances acetylcholine-induced Ca^<2+> signalling in rodent NG108-15 neuro blastoma cells (2007)
  • Author(s): Higashida, H., Bowden, S. E. H., Yokoyama, S. Salmina, A., Hashii, M., Hoshi, N., Zhang, J.-S., Knyjnik, R., Noda, M., Zhong, Z. G., Jin, D., Higashida, K., Takeda, H., Akita, T., Kuba, K., Yamagishi, S., Shimizu, N. Takasawa, S., Okamoto, H. and Robbins, J.
  • Journal Title: Neurosci Res. 57 Pages: 339-346
  • NAID: 10024413034
  • Peer Reviewed
• [Journal Article] Bidirectional Ca^<2+>- coupling of mitochondria with the end oplasmic reticulum and regulation of multimodal Ca^<2+> entries in rat brown adipocytes (2007)
  • Author(s): Kuba, M., Higure, Y., Susaki, H., Hayato, R. and Kuba, K.
  • Journal Title: Amer. J. Physiol. 292
  • Peer Reviewed
• [Journal Article] Bidirectional Ca^<2+> coupling of mitochondria With the endoplasimic reticulum and regulation of multimodal Ca^<2+> entries in rat brown adipocytes (2007)
  • Author(s): Kuba, M.
  • Journal Title: American Journal of Physiology, Cell Physiology 292
• [Journal Article] Enhancement of Ca^<2+> release by cyclic ADP-ribose in frog motor nerve terminals. (2007)
  • Author(s): Hachisuka, J.
  • Journal Title: Neuroscience 146 Pages: 123-131
• [Journal Article] Overexpression of human CD38/ADP-ribosyl cyclase enhances acetylcholine-induced Ca^<2+> signalling in rodent NG108-15 neuroblastoma cells (2007)
  • Author(s): Higashida, H.
  • Journal Title: Neuroscience Research 57 Pages: 339-346
• [Presentation] Bidirectional Ca^<2+> coupling between endoplasmic reticulum,mito-chondria and multimodal regulation of plasmalemmal Ca^<2+> entry in rat brown adipocytes (2008)
  • Author(s): Hayato, R., Higure, Y., Kuba, M. and Kuba, K.
  • Organizer: 第85回日本生理学会大会
  • Place of Presentation: 東京都
  • Year and Date: 2008-03-25
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Effects of high fat diet and cholic acids on adrenergic Ca^<2+> signaling and thermogenesis in brown adipocytes (2008)
  • Author(s): R. Hayato, Y. Higure, M. Kuba and K. Kuba
  • Organizer: 第85回日本生理学会
  • Place of Presentation: 東京
  • Year and Date: 2008-03-25
• [Presentation] Bile acid intake enhances noradrenaline-induced Ca^<2+> signaling and thermogenesis in brown adipocytes of high fat-fed mice (2007)
  • Author(s): Hayato, R., Higure, Y., Kuba, M. and Kuba, K.
  • Organizer: 第84回日本生理学会大会
  • Place of Presentation: 大阪市
  • Year and Date: 2007-03-20
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Sequential activation of Ca^<2+> release at mitochondria and ER and plasmalemmal Ca^<2+> entry by the β-action of noradrenaline in rat brown adipocytes (2007)
  • Author(s): Higure, Y., Hayato, R., Kuba, M. and Kuba, K.
  • Organizer: 第84回日本生理学会大会
  • Place of Presentation: 大阪市
  • Year and Date: 2007-03-20
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] acid intake enhances noradrenaline-induced Ca^<2+> signaling and thermogenesis in brown adipocytes of high fat-fed mice. (2007)
  • Author(s): Hayato, R., Higure, Y., Kuba, M., Kuba, K. Bile
  • Organizer: The Proceedings of the 84th Annual Meeting.
  • Place of Presentation: Osaka, Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Sequential activation of Ca^<2+> release at mitochondria and ER and plasrnalemmal Ca^<2+> entry by the β-action of noradrenaline in rat brown adipocytes. (2007)
  • Author(s): Higure, Y., Hayato, R., Kuba, M., Kuba, K.
  • Organizer: The Proceedings of the 84th Annual Meeting.
  • Place of Presentation: Osaka, Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Bidirectional Ca^<2+> coupling between endoplasmic reticulum, Mitochon dria and multimodal regulation of plasmalemmal Ca^<2+> entry in rat brown adi pocytes. (2007)
  • Author(s): Hayato, R., Higure, Y., Kuba, M., Kuba, K.
  • Organizer: The Proceedings of the 85th Annual Meeting.
  • Place of Presentation: Tokyo, Japan
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Functional Ca^<2+> coupling between the endoplasmic reticulum,mitochondria and the plasma membrane in rat brown adipocytes (2006)
  • Author(s): Hayato, R., Higure, Y., Kuba, M. and Kuba, K.
  • Organizer: The 63th Congress of the Federation of Asian and Oceanin Physiological Societies
  • Place of Presentation: 韓国、ソウル
  • Year and Date: 2006-10-16
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Activation of multimodal plasmalemmal Ca^<2+> entries via mitochondrial uncoupling by the β-action of noradrenaline in rat brown adipocytes (2006)
  • Author(s): Higure, Y., Hayato, R., Kuba, M. and Kuba, K.
  • Organizer: The 63th Congress of the Federation of Asian and Oceanin Physiological Societies
  • Place of Presentation: 韓国、ソウル
  • Year and Date: 2006-10-16
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Functional Ca^<2+> coupling between the endoplasmic reticulum, mitochondria and the plasma membrane in rat brown adipocytes. (2006)
  • Author(s): Hayato, R., Higure, Y., Kuba, M., Kuba, K.
  • Organizer: The 63th Congress of the Federation of Asian and Oceanin Physiological Societies.
  • Place of Presentation: Seoul, Korea
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Activation of multimodal plasmalemmal Ca^<2+> entries via mitochondrial uncoupling by the β-action of noradrenaline in rat brown adipocytes. (2006)
  • Author(s): Higure, Y., Hayato, R., Kuba, M., Kuba, K.
  • Organizer: The 63th Congress of the Federation of Asian and Oceanin Physiological Societies.
  • Place of Presentation: Seoul, Korea
  • Description: 「研究成果報告書概要(欧文)」より