| Project/Area Number |
17390045
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Medical pharmacy
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| Research Institution | Nagoya City University |
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Principal Investigator |
IMAIZUMI Yuji Nagoya City University, Graduate School of Pharmaceutical Sciences, Professor (60117794)
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| Co-Investigator(Kenkyū-buntansha) |
OHYA Susumu Nagoya City University, Graduate School of Pharmaceutical Sciences, Associate Professor (70275147)
YAMAMURA Hisao Nagoya City University, Graduate School of Pharmaceutical Sciences, Research Associate (80398362)
TOGARI Akihumi Aichi Gakuin University, School of Dentistry, Professor (80126325)
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| Project Period (FY) |
2005 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥16,100,000 (Direct Cost: ¥14,900,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2007: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2006: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2005: ¥6,900,000 (Direct Cost: ¥6,900,000)
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| Keywords | calcium-activated potassium channel / BK channel / SK channel / potassium channel opener / ryanodine receptor / caveolae / drug development / potential sensitive fluorescent / カルシウム活性化カリウムチャネル / TASKチャネル / ピマル酸 / 心筋ミトコンドリア / 心筋保護作用 / 間質細胞 / ペースメーカー細胞 |
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| Research Abstract |
In excitable cells, such as CNS neurons, negative feedback regulation systems for intracellular Ca^<2+> homeostasis work to prevent Ca^<2+> overlord, when excess excitability and resulting excess Ca^<2+> influx occurs. Activation of Ca^<2+> activated K+ (Kca) channels is know to be one ` of the most important components responsible for the negative feedback regulation of [Ca2^+]_i in excitable cells. This project was undertaken to elucidate the molecular mechanism for the regulation of Kca channel activity and to search changes in the regulation diseases. The goal of this project is to find out molecular seeds targeting on K_ca channels in some diseases. The following development was obtained during the research period. (1) It was found that small conductance K_ca (SK) channel in vascular endothelial cell lines originally derived from bovine blood-brain barrier has significant functional role in endothelial; proliferation stimulated by ATP presumably released from astrocytes in CNS. (J
… More
BC,2006; J Pharmacol Sci, 104, 2007). (2) The deep impact of ryanodine receptor type2 (RyR2) to the mechanism for negative feedback regulation of [Ca^<2+>], via spontaneous Ca^<2+> release(Ca^<2+> spark) from sarcoplasmic reticulum and subsequent activation of large conductance Kca (BK) channel was found using urinary bladder smooth muscle cells from wild type and RyR2 heterozygous KO mice. A line of evidence indicates that RyR2 contributes to the bladder continent as 'a key molecule regulating resting membrane potential and muscular tonus as well as excitation-contraction coupling (J Physiol, 2007, J Pharmacol Sci, 103, 2007). (3) It was found that potential sensitive oxonol dyes act as potent BK channel openers. It is the first synthesized compound which shows opening property selective to BK81 and 84 subunits over BK62. The oxonol compounds may be a seed of 8 subunit selective BK channel opener (Mol Pharmacol, 2007). (4) It has been known that the contractile responses of isolated large arteries from spontaneously hypertensive rats (SHR) to agonists are markedly potentiated in low pH bathing solution. It was found that the enhanced expression of BK channels in arterial smooth muscles of SHR and its sensitivity to extracellular pH are responsible for the acid pH induced potentiation of contraction (Am J Physiol, 2007). Less
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