カルシウムシグナリングと小脳シナプス回路発達

2004 Fiscal Year Annual Research Report

• Project/Area Number: 15016001
• Research Institution: HOKKAIDO UNIVERSITY
• Principal Investigator: 渡辺 雅彦 北海道大学, 大学院・医学研究科, 教授 (70210945)
• Co-Investigator(Kenkyū-buntansha): 深谷 昌弘 北海道大学, 大学院・医学研究科, 助手 (10360900)
• Keywords: シナプス / 発達 / 小脳 / グルタミン酸受容体 / 登上線維 / 平行線維 / プルキンエ細胞 / カルシウムチャネル

Research Abstract

NMDA型グルタミン酸受容体はGluRζ1(NR1)とGluRε(NR2)サブユニットからなり、両者の共発現は受容体の機能発現、翻訳後輸送、シナプス発現、受容体蛋白の安定性に不可欠である。大脳シナプスにはNMDA受容体が豊富に発現し、その活動依存的なカルシウム流入がシナプス回路改築、シナプス可塑性、細胞死などを制御している。しかし、小脳プルキンエ細胞はGluRεサブユニットの発現を欠失するため、機能的なNMDA受容体を持たない例外的なニューロンである。小脳プルキンエ細胞のシナプス回路発達が平行線維と登上線維の間の激しい競合の上に成り立っている事実を考慮すれば、何らかのカルシウム流入装置がその発達を制御している可能性がある。
そこで、プルキンエ細胞に豊富に発現するP/Q型カルシウムチャネルに着目し、そのチャネル本体を構成するα1Aサブユニットの遺伝子欠損マウスにおけるシナプス回路網の変化を追求した。その結果、本来遠位樹状突起のみを支配する平行線維の支配領域が近位樹状突起と細胞体にまで拡大していた。反対に、登上線維の支配領域はより近位部へと退縮していた。さらに、本来は単一の登上線維が独占的支配を確立している近位樹状突起において、複数の登上線維が混在する形で多重支配となっていた。これらの事実は、P/Q型カルシウムチャネルが1本の主要な登上線維の強化分子機構としてその独占的支配を促進し、他の興奮性入力をその支配領域から排除する分子機構であることを示唆している。従って、活動依存的なカルシウム流入が脳におけるシナプス回路改築の共通原理であり、NMDA受容体を持たないプルキンエ細胞ではP/Q型カルシウムチャネルがその役割を担っていることを物語っている。

Research Products

• [Journal Article] Mammalian septin Sept2 modulates the activity of GLAST, a glutamate transporter in astrocytes. (2004)
  • Author(s): Kinoshita, N., Kimura, K., Matsumoto, N., Watanabe, M., Fukaya, M., Ide, C.
  • Journal Title: Genes Cells 9 Pages: 1-14
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Targeted disruption of the mouse 3-phosphoglycerate dehydrogenase gene causes severe neurodevelopmental defects and results in embryonic lethality. (2004)
  • Author(s): Yoshida, K., Furuya, S., Osuka, S., Mitoma, J., Shinoda, Y., Watanabe, M., Azuma, N., Tanaka, H., Hashikawa, T., Itohara, S., Hirabayashi, Y.
  • Journal Title: J.Biol.Chem. 279 Pages: 3573-3577
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Two distinct classes of muscarinic action on hippoccampal inhibitory synapses : M2-mediated direct suppression and M1/M3-mediated indirect suppression through endocannabinoid signaling. (2004)
  • Author(s): Fukudome, Y., Ohno-Shosaku, T., Matsui, M., Omori, Y., Fukaya, M., Taketo, M., Watanabe, M., Manabe, M., Kano, M.
  • Journal Title: Eur.J.Neurosci. 19 Pages: 2682-2692
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Blood-to-retina transport of creatine via creatine transporter (CRT) at the rat inner blood-brain barrier. (2004)
  • Author(s): Nakashima, T., Tomi, M., Katayama, K., Tachikawa, M., Watanabe, M., Terasaki, T., Hosoya, K.
  • Journal Title: J.Neurochem. 89 Pages: 1454-1461
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Changes of high-affinity choline transporter expression during degeneration and regeneration of hypoglossal nerves in mice. (2004)
  • Author(s): Oshima, S., Yamada, K., Shirakawa, T., Watanabe, M.
  • Journal Title: Neurosci.Lett. 97 Pages: 97-101
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Identification and characterization of novel developmentally regulated neural-specific proteins, BRINP family. (2004)
  • Author(s): Kawano H, Nakatani T, Mori T, Ueno S, Fukaya M, Abe A, Kobayashi M, Toda F, Watanabe M, Matsuoka I.
  • Journal Title: Mol Brain Res. 125 Pages: 60-75
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] P/Q-type Ca^<2+> channel α1A regulates synaptic competition on developing cerebellar Purkinje cells (2004)
  • Author(s): Miyazaki, M., Hashimoto, K., Shin H.-S., Kano, M., Watanabe, M.
  • Journal Title: J.Neurosci. 24 Pages: 1734-1743
• [Journal Article] GABAergic basket cells expressing cholecystokinin contain vesicular glutamate transporter type 3 (VGLUT3) in their synaptic terminals in hippocampus and isocortex of the rat. (2004)
  • Author(s): Somogyi, J., Baude, A., Omori, Y., Shimizu, H., Mestikawy, S.E., Fukaya, M., Ryuichi, S., Watanabe, M., Somogyi, P.
  • Journal Title: Eur.J.Neurosci. 19 Pages: 552-569
• [Journal Article] Distinct cellular expressions of creatine synthetic enzyme GAMT and creatine kinases uCK-Mi and CK-B suggest novel neuron-glial relationship for brain energy homeostasis. (2004)
  • Author(s): Tachikawa, M., Fukaya, M., Terasaki, T., Ohtsuki, S., Watanabe, M.
  • Journal Title: Eur.J.Neurosci. 20 Pages: 144-160
• [Journal Article] Immunolocalization of metabotropic glutamate receptor 1a (mGluR1a) in distinct classes of interneuron in the CA1 region of the rat hippocampus. (2004)
  • Author(s): Ferraguti, F., Cobden, P., Pollard, M., Cope, D., Shigemoto, R., Watanabe, M., Somogy, P.
  • Journal Title: Hippocampus 14 Pages: 193-215
• [Journal Article] Widespread expression of the AMPA receptor GluR2 subunit at glutamatergic synapses in the rat spinal cord and phosphorylation of GluR1 in response to noxious stimulation revealed with an antigen unmasking. (2004)
  • Author(s): Nagy, G.G., Al-Ayyan, M., Andrew, D., Fukaya, M., Watanabe, M., Todd, A.J.
  • Journal Title: J.Neurosci. 24 Pages: 5766-5777
• [Journal Article] NMDA Receptor GluRe/NR2 subunits are essential for postsynaptic localization and protein stability of GluRz1/NR1 subunit. (2004)
  • Author(s): Abe, M., Fukaya, M., Yagi, T., Mishina, M., Watanabe, M., Sakimura, K.
  • Journal Title: J.Neurosci. 24 Pages: 9292-9304
• [Journal Article] Lysophosphatidic acid and autotaxin stimulate cell motility of neoplastic and non-neoplastic cells through LPA1. (2004)
  • Author(s): Hama, K., Aoki, J., Fukaya, M., Kishi, Y., Sakai, T., Suzuki, R., Ohta, H., Yamori, T., Watanabe, M., Chun, J., Arai, H.
  • Journal Title: J.Biol.Chem. 279 Pages: 17634-17639
• [Journal Article] Functional expression of rat ABCG2 and its enhancement by astrocyte-derived soluble factors(s). (2004)
  • Author(s): Hori, S., Ohtsuki, S., Tachikawa, M., Kimura, N., Kondo, T., Watanabe, M., Nakashima, E., Terasaki, T.
  • Journal Title: J.Neurochem. 90 Pages: 526-536
• [Journal Article] Age-dependent enhancement of hippocampal long-term potentiation in knock-in mice expressing human apolipoprotein E4 instead of mouse apolipoprotein E. (2004)
  • Author(s): Kitamura, H.W., Hamanaka, H., Watanabe, M., Wada, K., Yamazaki, C., Fujita, S.C., Manabe, T., Nukina, N.
  • Journal Title: Neurosci.Lett. 369 Pages: 173-178
• [Journal Article] Defective function of GABA-containing synaptic vesicles in mice lacking the AP-3B cclathrin adaptor. (2004)
  • Author(s): Nakatsu, F., Okada, M., Mori, F., Kamazawa, N., Iwasa, H., Zhu, G., Kasagi, Y., Kamiya, H., Harada, A., Nishimura, K., Takeuchi, A., Miyazaki, T., Watanabe, M., Yuasa, S., Manabe, T., Wakabayashi, K., Kaneko, S., Saito, T., Ohno, H.
  • Journal Title: J.Cell Biol. 167 Pages: 293-302
• [Journal Article] Upreguration of GluR2 decrease intracellular Ca2+ following ischemia in developing gerbils. (2004)
  • Author(s): Oguro, K., Miyawaki, T., Yokota, H., Kato, K., Kamiya, T., Katayama, Y., Fukaya, M., Watanabe, M., Shimazaki, K.
  • Journal Title: Neurosci.Lett. 364 Pages: 101-105
• [Journal Article] Signaling complex formation of phospholipase Cb4 with mGluR1a and IP3 R1 at the perisynapse and endoplasmic reticulum in the mouse brain. (2004)
  • Author(s): Nakamura, M., Sato, K., Fukaya, M., Araishi, K., Aiba, A., Kano, M., Watanabe, M.
  • Journal Title: Eur.J.Neurosci 20 Pages: 2929-2944
• [Journal Article] A novel action of stargazin as an enhancer of AMPA receptor activity.
  • Author(s): Yamazaki, M., Ohno-Shosaku, T., Fukaya, M., Kano, M., Watanabe, M., Sakimura, K.
  • Journal Title: Neurosci.Res. (印刷中)
• [Journal Article] Synaptic distribution of the NR1, NR2A, and NR2B subunits of the NMDA receptor in the rat lumbar spinal cord revealed with an antigen unmasking technique.
  • Author(s): Nagy, G.G., Watanabe, M., Fukaya, M., Todd, R.
  • Journal Title: Eur.J.Neurosci (印刷中)
• [Journal Article] The delta2 "glutamate receptor is not activated by glutamate-like ligand.
  • Author(s): Hirai, H., Miyazaki, T., Mishina, M., Watanabe, M., Yuzaki, M.
  • Journal Title: EMBO report. (印刷中)
• [Journal Article] Evidence for creatine biosynthesis in Muller glial cells.
  • Author(s): Nakashima, T., Tomi, M., Tachikawa, M., Watanabe, M., Terasaki, T., Hosoya, K.
  • Journal Title: J.Neurochem (印刷中)
• [Journal Article] NR2-to-NR3B subunit conversion of NMDA receptor in early postnatal motoneurons.
  • Author(s): Fukaya, M., Hayashi, Y., Watanabe, M.
  • Journal Title: Eur.J.Neurosci (印刷中)
• [Journal Article] Control of synaptic connection by glutamate receptor d2 in the mature cerebellum.
  • Author(s): Takeuchi, T., Miyazaki, T., Watanabe, M., Mori, H., Sakimura, K., Mishina, M.
  • Journal Title: J.Neurosci. (印刷中)