Regulation of brain functions by Ca^<2+>/calmodulin-dependent protein kinase II activity

• Project/Area Number: 17500218
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neuroscience in general
• Research Institution: National Institute for Physiological Sciences
• Principal Investigator: YAMAGATA Yoko National Institute for Physiological Sciences, Department of Information Physiology, Assistant Professor, 生体情報研究系, 助教授 (20210338)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2006: ¥1,000,000 (Direct Cost: ¥1,000,000); Fiscal Year 2005: ¥2,600,000 (Direct Cost: ¥2,600,000)
• Keywords: Signal Transduction / Neuroscience / Biomolecule / Physiology / Central Nervous System

Research Abstract

Ca^<2+>/calmodulin-dependent protein kinase II (CaMKII) is one of the most abundant protein kinase in the central nervous system and a key mediator of intracellular Ca^<2+> in response to various stimuli. CaMKII is involved in many neuronal functions including synaptic plasticity and higher brain functions. However, which protein function of CaMKII, i.e., protein kinase activity, calmodulin-binding capacity or multimeric structure interacting with other proteins, is responsible for such neuronal functions remains to be determined yet. To clarify specifically the role of protein kinase activity of CaMKII and its substrate protein phosphorylation, we engineered knock-in mice with the inactivated a subunit of CaMKII by replacing Lys-42 with Arg-42. As expected, CaMKII activity was selectively reduced, while CaMKII subunit protein levels were comparable to those of wild type controls in homozygous mutants. In situ hybridization revealed normal expression patterns of CaMKII subunit mRNAs, including dendritic localization of CaMKIIα mRNA in homozygous mutants. Electrophysiological analysis using acute hippocampal slices and cell biological study using cultured hippocampal neurons revealed abnormal synaptic plasticity but normal basal synaptic transmission in hippocampus in homozygous mutants. In addition, hippocampus-dependent learning deficit was also observed in these mice. These results indicate that protein kinase activity of CaMKIIα and its substrate protein phosphorylation are essential for maintaining normal hippocampal functions. Such a functionally deficient CaMKIIα mutant mouse will serve as a powerful tool in search for molecular details for activity-dependent synaptic plasticity.

Research Products

• [Journal Article] 脳内におけるリン酸化シグナル伝達-Ca^<2+>/カルモジュリン依存性プロテインキナーゼ IIの新たな役割. (2007)
  • Author(s): 山肩葉子
  • Journal Title: Clinical Neuroscience 25 Pages: 260-261
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Phosphorylation-dependent signal transduction in the brain-A new role of Ca2+/calmodulin-dependent protein kinase II [in Japanese] (2007)
  • Author(s): Yamagata, Y.
  • Journal Title: Clinical Neuroscience 25 Pages: 260-261
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] 脳内におけるリン酸化シグナル伝達-Ca^<2+>/カルモジュリン依存性プロテインキナーゼIIの新たな役割 (2007)
  • Author(s): 山肩葉子
  • Journal Title: Clinical Neuroscience 25 Pages: 260-261
• [Journal Article] A mechanism for the Inactivation of Ca^<2+>/calmodulin-dependent protein kinase II during prolonged seizure activity and its consequence after the recovery from seizure activity in rats in vivo. (2006)
  • Author(s): Yamagata, Y., Imoto, K., Obata, K.
  • Journal Title: Neuroscience 140 Pages: 981-992
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The role of protein kinase activity of Ca^<2+>/calmodulin-dependent protein kinase II α brain functions. (2006)
  • Author(s): Yamagata, Y., Hatanaka, N., Sakagami, H., Imoto, K., Obata.K., Takao.K., Miyakawa.T., Yanagawa.Y.
  • Journal Title: 2006 Molecular and Cellular Cognition Society Meeting in Atlanta (on line)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The role of protein phosphorylation in brain functions revealed by Inactivated Ca^<2+>/calmodulin-dependent protein kinase II α knock-in mouse. (2006)
  • Author(s): Yamagata, Y., Hatanaka, N., Sakagami, H., Imoto.K., Obata, K., Takao, K., Miyakawa, T., Yanagawa, Y.
  • Journal Title: 2006 Neuroscience Meeting Planner, Society for Neuroscience (on line)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The role of CaMKII in neuronal functions revealed by inactivated knock-in mouse. (2006)
  • Author(s): Yamagata, Y., Sakagami, H., Imoto.K., Obata, K., Takao, K., Miyakawa.T., Yanagawa, Y.
  • Journal Title: Bull. Jpn. Soc. Neurochem. 45・2, 3 Pages: 355-355
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The role of Ca^<2+>/calmodulin-dependent protein kinase II in neuronal functions revealed by inactivated CaMKIIα knock-in mouse. (2006)
  • Author(s): Yamagata, Y., Sakagami, H., Imoto, K., Obata, K., Yanagawa, Y.
  • Journal Title: Neurosci. Res. 55, Suppl.1
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The role of Ca^<2+>/calmodulin-dependent protein kinase II (CaMKII) in neuronal activity revealed by inactivated CaMKIIαknock-in mouse. (2006)
  • Author(s): Yamagata, Y.
  • Journal Title: J. Physiol. Sci. 56, Suppl.
  • NAID: 130005448184
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The role of Ca^<2+>/calmodulin-dependent protein kinase II in epilepsy. (2006)
  • Author(s): Yamagata, Y.
  • Journal Title: J. Pharmacol. Sci. 100, Suppl. 1 Pages: 39-39
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A mechanism for the inactivation of Ca^<2+>/calmodulin-dependent protein kinase II during prolonged seizure activity and its consequence after the recovery from seizure activity in rats in vivo (2006)
  • Author(s): Yamagata, Y., Imoto, K., Obata, K.
  • Journal Title: Neuroscience 140 Pages: 981-992
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The role of protein kinase activity of Ca^<2+>/calmodulin- dependent protein kinase II a in brain functions (2006)
  • Author(s): Yamagata, Y., Hatanaka, N., Sakagami, H., Imoto, K., Obata, K., Takao, K., Miyakawa, T., Yanagawa, Y.
  • Journal Title: 2006 Molecular and Cellular Cognition Society Meeting in Atlanta, on line
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The role of protein phosphorylation in brain functions revealed by inactivated Ca^<2+>/calmodulin-dependent protein kinase II a knock-in mouse (2006)
  • Author(s): Yamagata, Y., Hatanaka, N., Sakagami, H., Imoto, K., Obata, K., Takao, K., Miyakawa, T., Yanagawa, Y.
  • Journal Title: 2006 Neuroscience Meeting Planner, Society for Neuroscience, on line
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The role of CaMKII in neuronal functions revealed by inactivated knock-in mouse (2006)
  • Author(s): Yamagata, Y., Sakagami, H., Imoto, K., Obata, K., Takao, K., Miyakawa, T., Yanagawa, Y.
  • Journal Title: Bull. Jpn. Soc. Neurochem. 45-2,3 Pages: 355-355
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The role of Ca^<2+>/calmodulin-dependent protein kinase II in neuronal functions revealed by inactivated CaMKIIα knock-in mouse (2006)
  • Author(s): Yamagata, Y., Sakagami, H., Imoto, K., Obata, K., Yanagawa, Y.
  • Journal Title: Neurosci. Res. 55-Suppl.1
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The role of Ca^<2+>/calmodulin-dependent protein kinase II (CaMKII) in neuronal activity revealed by inactivated CaMKIIα knock-in mouse (2006)
  • Author(s): Yamagata, Y.
  • Journal Title: J. Physiol. Sci. 56-Suppl
  • NAID: 130005448184
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The role of Ca2+/calmodulin-dependent protein kinase II in epilepsy (2006)
  • Author(s): Yamagata, Y.
  • Journal Title: J. Pharmacol. Sci. 100-Suppl.1 Pages: 39-39
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A mechanism for the inactivation of Ca^<2+>/calmodulin-dependent protei kinase II during prologed seizure activity and its consequence afte the recovery from seizure activity in rats in vivo. (2006)
  • Author(s): Yamagata, Y., Imoto, K., Obata, K.
  • Journal Title: Neuroscience 140 Pages: 981-992
• [Journal Article] The role of CaMKII in neuronal functions revealed by inactivated knock-in mouse. (2006)
  • Author(s): Yamagata, Y., Sakagami, H., Imoto, K., Obata, K., Takao, K., Miyakawa, T., Yanagawa, Y.
  • Journal Title: Bull. Jpn. Soc. Neurochem. 45・2,3 Pages: 355-355
• [Journal Article] The role of Ca^<2+>/calmodilin-dependent protein kinase II in neuronal functions revealed by inactivated CaMKIIα knock-in mouse. (2006)
  • Author(s): Yamagata, Y., Sakagami, H., Imoto, K., Obata, K., Yanagawa, Y.
  • Journal Title: Neurosci. Res. 55,Suppl.1
• [Journal Article] A mechanism for the inactivation of Ca2^<2+>/calmodulin-dependent protei kinase II during prolonged seizure activity and its consequence afte the recovery from seizure activity in rats in vivo. (2006)
  • Author(s): Yamagata, Y., Imoto, K., Obata, K.
  • Journal Title: Neuroscience (in press)
• [Journal Article] The role of Ca^<2+>/calmodulin-dependent protein kinase II (CaMKII) in neuronal activity revealed by inactivated CaMKIIα knock-in mouse. (2006)
  • Author(s): Yamagata, Y.
  • Journal Title: J.Physiol.Sci. 56,Suppl.
  • NAID: 130005448184
• [Journal Article] The role of Ca^<2+>/calmodulin-dependent protein kinase II in epilepsy (2006)
  • Author(s): Yamagata, Y.
  • Journal Title: J.Pharmacol.Sci. 100,Suppl.1 Pages: 39-39
• [Journal Article] The role of Ca^<2+>/calmodulin-dependent protein kinase II in neuronal activity and seizure. (2005)
  • Author(s): Yamagata, Y.
  • Journal Title: Bull. Jpn. Soc. Neurochem. 44・2, 3 Pages: 170-170
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Functional analyses of inactivated CaMKIIα knock-in mouse. (2005)
  • Author(s): Yamagata, Y., Hatanaka, N., Imoto, K., Obata, K., Yanagawa, Y.
  • Journal Title: Neurosci. Res. 52, Suppl.
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The role of Ca2+/calmodulin-dependent protein kinase II in neuronal activity and seizure (2005)
  • Author(s): Yamagata, Y.
  • Journal Title: Bull. Jpn. Soc. Neurochem. 44-2,3 Pages: 170-170
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Functional analyses of inactivated CaMKIIα knock-in mouse (2005)
  • Author(s): Yamagata, Y., Hatanaka, N., Imoto, K., Obata, K., Yanagawa, Y.
  • Journal Title: Neurosci. Res. 52-Suppl
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The role of Ca^<2+>/calmodulin-dependent protein kinase II in neuronal activity and seizure. (2005)
  • Author(s): Yamagata, Y.
  • Journal Title: Bull.Jpn.Soc.Neurochem. 44・2,3 Pages: 170-170
• [Journal Article] Functional analyses of inactivated CaMKIIα knock-in mouse. (2005)
  • Author(s): Yamagata, Y., Hatanaka, N., Imoto, Obata, K., Yanagawa, Y.
  • Journal Title: Neurosci.Res. 52,Suppl.
• [Patent(Industrial Property Rights)] 不活性型Ca^<2+>/カルモジュリン依存性プロテインキナーゼIIαノックイン動物および同ノックイン細胞
  • Inventor(s): 山肩葉子, 柳川右千夫
  • Industrial Property Rights Holder: 独立行政法人科学技術振興機構
  • Industrial Property Number: 2004-096995
  • Description: 「研究成果報告書概要(和文)」より