Regulation of signals by TRP channels audits physiological significauce

• Project/Area Number: 18390085
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Kyoto University
• Principal Investigator: MORI Yasuo Kyoto University, Graduate School of Engineering, Professor (80212265)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥15,080,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥1,080,000); Fiscal Year 2007: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2006: ¥10,400,000 (Direct Cost: ¥10,400,000)
• Keywords: signal transduction / channel / chemotaxis / inflammation / reactive oxygenspecies / チャンネル

Research Abstract

Chemokines mediate the recruitment of inflammatory cells such as neutrophils and monocytes at inflamed sites in injury or infection. Recently, patho-physiological significance of reactive oxygen species (ROS) has been recognized in inflammatory chemokine expression. Here, we demonstrate that the plasma membrane Ca^<2+>-permeable cation channel TRPM2 controls chemokine production in response to ROS in monocytes. In human monocytic cell line U937, hydrogen peroxide (H202) induces Ca^<2+> influx via TRPM2 channels that triggers Ca^<2+>-dependent activation of Pyk2 and amplifies Erk activation in Ras-dependent manner. The amplification of Erk signal leads to the nuclear translocation of nuclear factor-_KB (NF_KB) and the subsequence production of the chemokine interleukine-8 (IL-8), suggesting a pivotal role played by TRPM2 in ROS-induced IL-8 production in monocytes. Monocytes isolated from TRPM2 knockout mice show significantly suppressed elevation of intracellular Ca^<2+> concentration and production of the macrophage inflammatory protein 2 (MIP-2), a murine counterpart of IL-8, upon stimulation with H2O2. In dextran sulfate sodium-induced experimental colitis used as a model for inflammation, MIP-2 production, neutrophil infiltration, and ulceration were significantly attenuated by TRPM2 defeciency. These findings suggest that Ca^<2+> inflax via TRPM2 channels amplifies ROS-induced Erk/NF_KB activation to control chemokine production, playing a key role in aggravation of inflammation.

Research Products

• [Journal Article] RIM1 confers sustained activity and neurotransmitter vesicle anchoring to presynaptic Ca^<2+>channels. (2007)
  • Author(s): Kiyonaka S, Wakamori M, Miki T, Uriu Y, Nonaka M, Bito H, Beedle AM, Mori E, Hara Y, De Waard M, Kanagawa M, Itakura M, Takahashi M, Campbell KP & Mori Y
  • Journal Title: Nature Neurosci. 10 Pages: 691-701
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Gα_<12/13>-mediated upregulation of TPPC6 negatively regulates endothelin-induced cardiac myofibroblast formation and collagen synthesis through NFAT activation. (2007)
  • Author(s): Nishida M, Onohara N, Sato Y, Suda R, Ogushi M, Tanabe S, Inoue R, Mori Y & Kurose H
  • Journal Title: J. Biol. Chem. 282 Pages: 23117-23128
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] TRPM7 channels in hippocampal neurons detect levels of extracellular divalent cations. (2007)
  • Author(s): Wei W-L, Sun H-S, Olah ME, Sun XiuJun, Czerwinska E, Czerwinski W, Mori Y, Orser BA, Xiong Z-G, Jackson MF, Tymianski M & MacDonald JF
  • Journal Title: Proc. Natl. Acad. Sci. USA. 104 Pages: 16323-16328
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Mutation associated with an autosomal dominant cone-rod dystrophy CORD7 modifies RIM1-mediated modulation of voltage-dependent Ca^<2+>channels. (2007)
  • Author(s): Miki T, Kiyonaka S, Uriu Y, De Waard M, Wakamori M, Beedle AM, Campbell KP & Mori Y
  • Journal Title: Channels 1 Pages: 144-147
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Galan-mediated upregulation of TPPC6 negatively regulates endothelin-induced cardiac myofibroblast formation and collagen synthesis through NFAT activation. (2007)
  • Author(s): Nishida, M, Onohara, N, Sato, Y, Suda, R, Ogushi, M, Tanabe, S, Inoue, R, Mori, Y, Kurose, H
  • Journal Title: J. Biol. Chem 282 Pages: 23117-23128
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] TRPM7 channels in hippocampal neurons detect levels of extracellular divalent cations (2007)
  • Author(s): Wei, W-L, Sun, H-S, Olah, ME, Sun, XiuJun, Czerwinska, E, Czerwinski, W, Mon, Y, Orser, BA, Xiong, Z-G, Jackson, MF, Tymianski, M, MacDonald, JF
  • Journal Title: Proc. NatL Acad. Sci. USA 104 Pages: 16323-16328
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mutation associated with an autosomal dominant cone-rod dystrophy CORD7 modifies RIM1-mediated modulation of voltage-dependent Ca^<2+> channels. (2007)
  • Author(s): Miki, T, Kiyonaka, S, Uriu, Y, De, Waard, M, Wakamori, M, BeedleAM, Campbell, KP, Mori, Y
  • Journal Title: Channels 1 Pages: 144-147
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] RIMl confers sustained activity and neurotransmitter vesicle anchoring to presynaptic Ca2+ channels. (2007)
  • Author(s): Kiyonaka S, wakamori M, Miki T, Uriu Y, Nonaka M, Bito H, Beedle AM, Mori E, Hara Y, De Waard M, Kanagawa M, Itakura M, Takahashi M, Campbeil KP & Mori Y
  • Journal Title: Nature Neurosci. 10 Pages: 691-701
  • Peer Reviewed
• [Journal Article] TRPM7 channels in hippocampal neurons detect levels of extracellular divalent cations. (2007)
  • Author(s): Wei W-L, Sun H-S, Olah ME, Sun XiuJun, Czerwinska E, Czerwinski W, Mori Y, Orser BA, Xiong Z-G, Jackson MF, Tymianski M & MacDonald JF
  • Journal Title: Proc. Natl. Acad. Sci. USA 104 Pages: 16323-16328
  • Peer Reviewed
• [Journal Article] G-12/13-mediated upregulation of TPPC6 negatively regulates endothelin-induced cardiac myofibroblast formation and collagen synthesis Through NFAT activation. (2007)
  • Author(s): Nishida M, Onohara N, Sato Y, Suda R, Ogushi M, Tanabe S, Inoue R, Mori Y & Kurose H
  • Journal Title: J. Biol. Chem. 282 Pages: 23117-23128
  • Peer Reviewed
• [Journal Article] Coupling of STIMl to store-operated Ca2+ entry through its constitutive and inducible movement in the endoplasmic reticulum. (2007)
  • Author(s): Baba Y, Hayashi K, Wakamori M, Numaga T, Mori Y, Kurosaki T
  • Journal Title: Proc. Natl. Acad. Sci. USA 103 Pages: 16704-16709
• [Journal Article] Ca^<2+>/calmodulin dependent myosin light chain kinase is essential for activation of TRPC5 channels expressed in HEK cells. (2006)
  • Author(s): Shimizu S, Yoshida T, Wakamori M, Ishii M, Okada T, Takahashi M, Seto M, Sakurada K, Kiuchi Y & MoriY
  • Journal Title: J. Physiol. 570 Pages: 219-235
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] A functional AMPA receptor-calcium channel complex in the postsynaptic membrane. (2006)
  • Author(s): Kang, MG, Chen CC, Wakamori M, Hara Y, Mori Y & Campbell KP
  • Journal Title: Proc. Natl. Acad. Sci. USA. 103 Pages: 5561-5566
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] TRPM2 activation by cyclic ADP-ribose at body temperature is involved in insulin secretion. (2006)
  • Author(s): Togashi K, Hara Y, Higashi T, Konishi Y, Tominaga T, Mori Y & Tominaga M
  • Journal Title: EMBO J. 25 Pages: 1804-1815
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Nitric oxide activates TRP channels by cysteine S-nitrosylation. (2006)
  • Author(s): Yoshida T, Inoue R, Morii T, Takahashi N, Yamamoto S, Hara Y, Tominaga M, Shimizu S, Sato Y & Mori Y
  • Journal Title: Nature Chem. Biol. (Article) 2 Pages: 596-607
  • NAID: 130007038569
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Coupling of STIM1 to store-operated Ca^<2+>entry through its constitutive and Inducible movement in the endoplasmic reticulum. (2006)
  • Author(s): Baba Y, Hayashi K, Fujii Y, Mizushima A, Watarai H, Wakamori M, Numaga T, Mori Y, Iino M, Hikida M & Kurosaki T
  • Journal Title: Proc. Natl. Acad. Sci. USA. 103 Pages: 16704-16709
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Ca^<2+>/calmodulin dependent myosin light chain kinase is essential for activation of TRPC5 channels expressed in HEK cells. (2006)
  • Author(s): Shimizu, S, Yoshida, T, Wakamori, M, Ishii, M, Okada, T, Takahashi, M,Seto, M, Sakurada, K, Kiuchi, Y, Mori, Y
  • Journal Title: J. Physiol. 570 Pages: 219-235
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A functional AMPA receptor-calcium channel complex in the postsynaptic membrane (2006)
  • Author(s): Kang, MG, Chen, CC, Wakamori, M, Hara, Y, Mori, Y, Campbell, KP
  • Journal Title: Proc. Natl. Acad. Sci. USA 103 Pages: 5561-5566
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] TRPM2 activation by cyclic ADP-ribose at body temperature is involved in insulin secretion. (2006)
  • Author(s): Togashi, K, Ham, Y, Higashi, T, Konishi, Y, Tominaga, T, Mori, Tominaga, M
  • Journal Title: EMBO J. 25 Pages: 1804-1815
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Nitric oxide activates TRP channels by cysteine S-nitrosylation. (2006)
  • Author(s): Yoshida, T, Inoue, R, Morii, T, Takahashi, N, Yamamoto, S, Hara, Y, Tominaga, M, Shimizu, S, Sato, Y, Mori, Y
  • Journal Title: Nature Chem. Biol. 2 Pages: 596-607
  • NAID: 130007038569
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Coupling of STIMI to store-operated Ca^<2+> entry through its constitutive and inducible movement in the endoplasmic reticulum. (2006)
  • Author(s): Baba, Y, Hayashi, K, Fujii, Y, Mizushima, A, Watarai, H, Wakamori, M, Numaga, T, Mod, Y, lino, M, Hikida, M, Kurosaki, T
  • Journal Title: Proc. Natl. Acad. Sci. USA 103 Pages: 16704-16709
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Ca2+/calmodulin dependent myosin light chain kinase is essential for activation of TRPC5 channels expressed in HEK cells. (2006)
  • Author(s): Shimizu S, Yoshida T, Wakamori M, K, Kiuchi Y, Mori Y
  • Journal Title: J. Physiol. 570 Pages: 219-235
• [Journal Article] A functional AMPA receptor-calcium channel complex in the postsynaptic membrane. (2006)
  • Author(s): Kang, MG, Chen CC, Wakamori M, Hara Y, Mori Y, Campbell KP
  • Journal Title: Proc. Natl. Acad. Sci. USA 103 Pages: 5561-5566
• [Journal Article] TRPM2 activation by cyclic ADP-ribose at body temperature is involved in insulin secretion. (2006)
  • Author(s): Togashi K, Hara Y, Mori Y, Tominaga M
  • Journal Title: EMBO J. 25 Pages: 1804-1815
• [Journal Article] Nitric oxide activates TRP channels by cysteine S-nitrosylation. (2006)
  • Author(s): Yoshida T, Inoue R, Morii T, Takahashi N, Yamamoto S, Mori Y
  • Journal Title: Nature Chem. Biol. (Article) 2 Pages: 596-607
  • NAID: 130007038569
• [Journal Article] RIM1 confers sustained activity and neurotransmitter vesicle anchoring to presynaptic Ca^<2+> channels. (2001)
  • Author(s): Kiyonaka, S, Wakamori, M, Mild, T, thin, Y, Nonaka, M, Bito, H, Beadle, AM. Mori, E, Hara, Y, De, Waard, M, Kanagawa, M, Itakura, M, Takahashi, M, Campbell, KP, Mori, Y
  • Journal Title: Nature Neurosci. 10 Pages: 691-701
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] RIMl confers sustained activity and neurotransmitter vesicle anchoring to presynaptic Ca2+ channels.
  • Author(s): Kiyonaka S, Wakamori M, Miki T, Uriu Y, Nonaka M, Campbell KP, Mori Y
  • Journal Title: Nature Neurosci. (Article) (in press)
• [Presentation] Oxidative stress-activated Ca^<2+>channel TRPM2 mediates inflammation via chemokine production. (2007)
  • Author(s): 森 泰生
  • Organizer: Keystone Symposia
  • Place of Presentation: Colorado, USA
  • Year and Date: 2007-09-21
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Oxidative stress-activated Ca^<2+> channel TRPM2 mediates inflammation via chemokine production (2007)
  • Author(s): Yasuo, Mori
  • Organizer: Keystone Symposia
  • Place of Presentation: Colorado, USA
  • Year and Date: 2007-09-21
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] TRP channels activated by nitrosylation and oxidative cysteine modifications. (2007)
  • Author(s): 森 泰生
  • Organizer: 4th SFB 530 Colloquium, Spatio-temporal interactions of cellular signaling molecules
  • Place of Presentation: Homburg, Germany
  • Year and Date: 2007-05-18
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] TRP channels activated by nitrosylation and oxidative cysteine modifications (2007)
  • Author(s): Yasuo, Mori
  • Organizer: 4th SFB 530 Colloquium, Spatio-temporal interactions of cellular signaling molecules
  • Place of Presentation: Homburg, Germany
  • Year and Date: 2007-05-08
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] The active zone protein RIMI confers sustained activity and neurotransmitter vesicle anchoring to presynaptic Ca^<2+> channels. (2007)
  • Author(s): 森 泰生
  • Organizer: Calcium Channel Conference
  • Place of Presentation: Tahiti
  • Year and Date: 2007-04-03
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] The active zone protein RIMI confers sustained activity and neurotransmitter vesicle anchoring to presynaptic Ca^<2+> channels (2007)
  • Author(s): Yasuo, Mori
  • Organizer: Calcium Channel Conference
  • Place of Presentation: Tahit
  • Year and Date: 2007-04-03
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Physiological significance of Neuronal calcium channel complexes: Nitricoxide activates TRP channels by cysteine s-nitrosylation. (2006)
  • Author(s): 森 泰生
  • Organizer: The 4th congress of federation of Asian-Oceanian Neuroscience Societies
  • Place of Presentation: Hong Kong
  • Year and Date: 2006-11-02
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Physiological significance of Neuronal calcium channel complexes : Nitric oxide activates TRP channels by cysteine s-nitrosylation (2006)
  • Author(s): Yasuo, Mori
  • Organizer: The 4th congress of federation of Asian-Oceanian Neuroscience Societies
  • Place of Presentation: Hong Kong
  • Year and Date: 2006-11-02
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Regulation of Cellular Signals by TRP Channels. (2006)
  • Author(s): 森 泰生
  • Organizer: 3rd Singapore International Neuroscience Conference
  • Place of Presentation: Singapore
  • Year and Date: 2006-05-24
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Regulation of Cellular Signals by TRP Channels (2006)
  • Author(s): Yasuo, Mori
  • Organizer: 3rd Singapore International Neuroscience Conference
  • Place of Presentation: Singapore
  • Year and Date: 2006-05-24
  • Description: 「研究成果報告書概要(欧文)」より