| Project/Area Number |
12144207
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Osaka University |
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Principal Investigator |
KURACHI Yoshihisa Osaka University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (30142011)
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| Co-Investigator(Kenkyū-buntansha) |
ISHII Masaru Osaka University, Graduate School of Medicine, Assistant professor, 免疫異常疾患研究所, 研究員 (10324758)
HIBINO Hiroshi Osaka University, Graduate School of Medicine, Assistant professor, 医学系研究科, 助手 (70314317)
MARUYAMA Yoshio Tohoku University, Graduate School of Medicine, Professor, 医学系研究科, 教授 (00133942)
種本 雅之 大阪大学, 医学系研究科, 助手 (40303945)
稲野辺 厚 大阪大学, 医学系研究科, 助手 (00270851)
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| Project Period (FY) |
2000 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥147,300,000 (Direct Cost: ¥147,300,000)
Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2004: ¥36,200,000 (Direct Cost: ¥36,200,000)
Fiscal Year 2003: ¥34,100,000 (Direct Cost: ¥34,100,000)
Fiscal Year 2002: ¥37,000,000 (Direct Cost: ¥37,000,000)
Fiscal Year 2001: ¥38,500,000 (Direct Cost: ¥38,500,000)
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| Keywords | Inwardly rectifying K+ channels / Water channels / Epithelial cells / homeostasis / Kidney / Glial cells / 内向き整流カリウムチャネル / グリア細胞 |
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| Research Abstract |
We examined physiological roles of inwardly-rectifying K^+-channels in vectorial-transports of epithelia, by analyzing (1) polarized kralization of the channels in various cells, and (2) regulation of their function. We investigated Kir4.1 and Kir5.1 for (1) and, additionally, ATP-sensitive K^+-channels (K_<ATP>) and G-protein gated K^+-channels (K_G) for (2).
(A) Specific localization of Kir4.1 and Kir5.1 and their function
We found three multimers, Kir4.1-homomer, Kir5.1-homomer, and Kir41/5.1-heteromer, existed in vivo and differentially distributed in specific membrane domains of glia and epithelia. We further identified diversity of subunit-assembly and distribution functionally contributed to vectorial-transports of K^+.
(a) In renal epithelia, the heteromer distributes at their basolateral membrane and acts as an "intracellular pH-sensor'.
(b) In cochlea, the two homomers occur in distinct tissues and mediate K^+-circulation essential for hearing.
(c) In brain astrocytes and retinal
… More
Muller cells, Kir4.1-homomer and Kir4.1/5.1-heteromer differentially distribute in pweicascular and perisynaptic processes and play distinct roles in K^+-buffering.
(d) These channels are targeted to the membrane by dystrophin-associated protein-complex, and clustered in a microdomain called "lipid-raft' where they are functionally coupled to water channel AQP4.
(B) Regulation of function of K_G
Cardiac K_G has a characteristic voltage-dependent gate-property called "relaxation". We identified its molecular basis as followings-
(a) The relaxation is dramatically regulated by "RGS(Regulator of G-protein Signaling)".
(b) This regulation involves PIP_3-inhibition of RGS and its reversal by Ca^<2+>/calmodulin.
(c) PIP_3 and Ca^<2+>/calmoclulin competitively bind RGS and reciprocally regulate its action.
(C) Structure and function of K_<ATP>, (Kir6.x+SUR)
We established structure-model of SUR and explained mechanism of regulation of K_<ATP>, by intracellular ADP. Furthermore, we found that dimerization of two nucleotide-binding domains was essential for opening the channel-pore.
We found that Ca^<2+> released to inside of nucleus by NADDP receptor-channel on nuclear envelope mediated transit of information from cytosol to nucleus. Less
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