Ca^<2+> channelplexes : assembly in the membrane and physiological significance

2009 Fiscal Year Final Research Report

• Project/Area Number: 17081011
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyoto University
• Principal Investigator: MORI Yasuo Kyoto University, 大学院・工学研究科, 教授 (80212265)
• Co-Investigator(Kenkyū-buntansha): FUJIMOTO Toyoshi 名古屋大学, 大学院・医学系研究科, 教授 (50115929) ; WAKAMORI Minoru 東北大学, 大学院・歯学研究科, 教授 (50222401) ; HARA Yuji アイオワ大学, 医学部, ポスドク (60362456)
• Project Period (FY): 2005 – 2009
• Keywords: Ca^<2+>チャネル / 分子複合体 / 膜分子集積 / シグナル伝達 / バイオセンサー

Research Abstract

Ca^<2+> as a second messenger controls a wide variety of biological responses and contributes to formation of tissues such as bones, thereby playing a central role in regulating "homeostasis" at whole body, tissue, and cell levels. In my research, I have focused on voltage-dependent Ca^<2+> channels (VDCCs) and transient receptor potential (TRP) channels to aim at understanding mechanisms, that underlie formation and assembly at the biomembrane of Ca^<2+> channel protein complexes (Ca^<2+> channelplexes), and their physiological significance. Firstly, I have unveiled several unique activation mechanisms, that regulate cellular signal transduction for TRP Ca^<2+>-permeable caion channels. Secondly, I have demonstrated that channel proteins act not only as Ca^<2+>-permeating apparatus but also as assembly centers for receptors, signal-regulating proteins, and scaffolding proteins. Thirdly, important roles of Ca^<2+> channel protein complexes via formation of feedback regulation pathways in signal transduction have been demonstrated. Finally, I have also shown physiological significance of Ca^<2+> channelplexes at tissue levels. TRPC3 channelplexes in B lymphocyte activation and P/Q type VDCCplexes in presynaptic vesicle fusion are examples of the outcome of this study. Thus, my study clarifies how individual Ca^<2+> channels play roles in unique cellular responses.

Research Products

• [Journal Article] TRPM1 is a component of the retinal ON bipolar cell transduction channel in the mGluR6 cascade. (2010)
  • Author(s): Koike C, Obara T, Uriu Y, Numata T, Sanuki R, Miyata K, Koyasu T, Ueno S, Funabiki K, Tani A, Ueda H, Kondo M, Mori Y, Tachibana M, Furukawa T.
  • Journal Title: Proc. Natl. Acad. Sci. USA 107 Pages: 332-337
  • Peer Reviewed
• [Journal Article] Involvement of Ca^<2+> Channel Synprint Site in Synaptic Vesicle Endocytosis. (2010)
  • Author(s): Watanabe H, Yamashita T, Saitoh N, Kiyonaka S, Iwamatsu A, Campbell KP, Mori Y, Takahashi T.
  • Journal Title: J. Neurosci. 30 Pages: 655-660
  • Peer Reviewed
• [Journal Article] An in vivo fluorescent sensor reveals intracellular Ins(1, 3, 4, 5)P(4) dynamics in single cells. (2010)
  • Author(s): Sakaguchi R, Tainaka K, Shimada N, Nakano S, Inoue M, Kiyonaka S, Mori Y, Morii T.
  • Journal Title: Angew. Chem. Int. Ed. 17 Pages: 7381-7386
  • Peer Reviewed
• [Journal Article] A pathogenic C-terminus-truncated Polycistin-2 mutant enhances receptor-activated Ca^<2+> entry via association with TRPC3 and TRPC7. (2009)
  • Author(s): Miyagi K, Kiyonaka S, Yamada K, Miki T, Mori E, Kato K, Numata T, Sawaguchi Y, Numaga T, Kimura T, Kanai Y, Kawano M, Wakamori M, Nomura H, Koni I, Yamagishi M, Mori Y.
  • Journal Title: J. Biol. Chem. 284 Pages: 34400-34412
  • Peer Reviewed
• [Journal Article] Suppression of hippocampal TRPM7 protein prevents delayed neuronal death in brain ischemia. (2009)
  • Author(s): Sun H-S, Jackson MF, Martin LJ, Jansen K, Teves L, Cui H, Kiyonaka S, Mori Y, Jones M, Forder JP, Golde TE, Orser BA, MacDonald JF, Tymianski M.
  • Journal Title: Nature Neurosci. 12 Pages: 1300-1307
  • Peer Reviewed
• [Journal Article] Targetted disruption of the voltage-dependent Ca^<2+> channelα-2/δ-1 subunit. (2009)
  • Author(s): Fuller-Bicer GA, Varadi G, Koch SE, Ishii M, Bodi I, Kadeer N, Muth JN, Mikala G, Petrashevskaya NN, Jordan MA, Zhang SP, Qin N, Flores CM, Isaacsohn I, Varadi M, Mori Y, Jones WK, Schwartz A.
  • Journal Title: Am. J. Physiol. Heart Circ. Physiol. 297 Pages: H117-124
  • Peer Reviewed
• [Journal Article] Synergistic activation of vascular TRPC6 channel by receptor and mechanical stimulation via PLC/diacylglycerol and PLA-2/￡s-hydroxylase/20-HETE pathways. (2009)
  • Author(s): Inoue R, Jensen LJ, JianZ, Shi J, Hai L, Lurie AI, Henriksen FH, Salmonsson M, Morita H, Kawarabayashi Y, Mori M, Mori Y, Ito Y.
  • Journal Title: Circ Res. 104 Pages: 1399-1409
  • Peer Reviewed
• [Journal Article] STIM protein coupling in the activation of Orai channels. (2009)
  • Author(s): Wang Y, Deng X, Zhou Y, Hendron E, Mancarella S, Ritchie MF, Tang XD, Baba Y, Kurosaki T, Mori Y, Soboloff J, Gill DL.
  • Journal Title: Proc. Natl. Acad. Sci. USA 106 Pages: 7391-7396
  • Peer Reviewed
• [Journal Article] TRPM2 functions as lysosomal Ca^<2+> release channel in β-cells. (2009)
  • Author(s): Lange I, Yamamoto Y, Partida-Sanchez S, Mori Y, Fleig A, Penner R.
  • Journal Title: Science Signaling 2 Pages: ra23
  • Peer Reviewed
• [Journal Article] Tetrameric Orail is a teardrop-shaped molecule with a long, tapered cytoplasmic domain. (2009)
  • Author(s): Maruyama Y, Ogura T, Mio K, Kato K, Kaneko T, Kiyonaka S, Mori Y, Sato C.
  • Journal Title: J. Biol. Chem. 284 Pages: 13676-13685
  • Peer Reviewed
• [Journal Article] Selective and direct inhibition of TRPC3 channels underlies biological activities of a pyrazole compound. (2009)
  • Author(s): Kiyonaka S, Kato K, Nishida M, Mio K, Numaga T, Sawaguchi Y, Yoshida T, Wakamori M, Mori E, Numata T, Ishii M, Takemoto H, Ojida A, Watanabe K, Uemura A, Kurose H, Morii T, Kobayashi T, Sato Y, Sato C, Hamachi I, Mori Y
  • Journal Title: Proc. Natl. Acad. Sci. USA 106 Pages: 5400-5405
  • Peer Reviewed
• [Journal Article] Changes in temperature preferences and energy homeostasis in dystroglycan mutants. (2009)
  • Author(s): Takeuchi K, Nakano Y, Kato U, Kaneda M, Aizu M, Awano W, Yonemura S, Kiyonaka S, Mori Y, Yamamoto D, Umeda M.
  • Journal Title: Science 323 Pages: 1740-1743
  • Peer Reviewed
• [Journal Article] Ca^<2+>-dependent induction of TRPM2 currents in hippocampal neurons. (2009)
  • Author(s): Olah ME, Jackson MF, Li H, Perez Y, Sun HS, Kiyonaka S, Mori Y, TymianskiM, Macdonald JF.
  • Journal Title: J. Physiol. 587 Pages: 965-979
  • Peer Reviewed
• [Journal Article] Molecular characterization of TRPA1 channel activation by cysteine-reactive inflammatory mediators. (2008)
  • Author(s): Takahashi N, Mizuno Y, Kozai D, Yamamoto S, Kiyonaka S, Shibata T, Uchida K, Mori Y.
  • Journal Title: Channels 2 Pages: 287-298
  • Peer Reviewed
• [Journal Article] TRPM2-mediated Ca^<2+> influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration (2008)
  • Author(s): Yamamoto S, Shimizu S, Kiyonaka S, Takahashi N, Wajima T, Hara Y, Negoro T, Hiroi T, Kiuchi Y, Okada T, Kaneko S, Lange I, Fleig A, Penner R, Nishi M, Takeshima H, Mori Y.
  • Journal Title: Nature Med. 14 Pages: 738-747
  • Peer Reviewed
• [Journal Article] The TRPM2 channel is a swelled, bell-shaped molecule with a protrusion on the cytoplasmic end. (2007)
  • Author(s): Maruyama Y, Ogura T, Mio K, Kiyonaka S, Kato K, Mori Y, Sato C
  • Journal Title: J. Biol. Chem. 282 Pages: 36961-36970
  • Peer Reviewed
• [Journal Article] TRPM7 a possible extracellular divalent cati on sensor in hippocampal neurons. (2007)
  • Author(s): Wei W-L, Olah ME, 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] 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
  • 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
  • Peer Reviewed
• [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
  • Peer Reviewed
• [Journal Article] TRPC3 and TRPC6 are essential for angiotensin II-induced cardiac hypertrophy. (2006)
  • Author(s): Onohara N, Nishida M, Inoue R, Kobayashi H, Sumimoto H, Sato Y, Mori Y, Nagao T, Kurose H
  • Journal Title: EMBO J. 25 Pages: 5305-5316
  • 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
  • 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. 2 Pages: 596-607
  • Peer Reviewed
• [Journal Article] Native TRPC7 channel activation by an inositol trisphosphate receptor-dependent mechanism. (2006)
  • Author(s): Vazquez G, Bird GSJ, Mori Y, Putney JW
  • Journal Title: J. Biol. Chem. 281 Pages: 25250-25258
  • Peer Reviewed
• [Journal Article] Cyclosporin and Timothy syndrome increase mode 2 gating of Ca_V1.2 calcium channels through aberrant phosphorylation of S6 helices. (2006)
  • Author(s): Erxleben C, Liao Y, Gentile S, Chin D, Gomez-Alegria C, Mori Y, Birnbaumer L, Armstrong DL.
  • Journal Title: Proc. Natl. Acad. Sci. U.S.A. 103 Pages: 3932-3937
  • 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
  • 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
  • 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
  • Peer Reviewed
• [Journal Article] The role of canonical transient receptor potential 7 (TRPC7) in B-cell receptor-activated channels. (2005)
  • Author(s): Lievremont J-P, Numaga T, Vazquez G, Lemonnier L, Hara Y, Mori E, Trebak M, Moss SE, Bird GS, Mori Y, Putney Jr JW
  • Journal Title: J. Biol. Chem. 280 Pages: 35346-35351
  • Peer Reviewed
• [Journal Article] Differential redox regulation of ORAI channels : a mechanism to tune cellular calcium responses.
  • Author(s): Bogeski I, Kummerow C, Al-Ansary D, Koehler R, Schwarz EC, Kozai D, Takahashi N, Peinelt C, Griesemer D, Bozem B, Mori Y, Hoth M, Niemeyer BA
  • Journal Title: Science Signaling (in press)
  • Peer Reviewed
• [Journal Article] Ca^<2+> influx and protein scaffolding via TRPC3 sustain PKCβ and ERK activation in B cells.
  • Author(s): Numaga T, Nishida M, Kiyonaka S, Kato K, Katano K, Mori E, Kurosaki T, Inoue R, Hikida T, Putney Jr JW, Mori Y
  • Journal Title: J. Cell Sci. (in press)
  • Peer Reviewed