| Project/Area Number |
17390056
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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 |
General physiology
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| Research Institution | Hiroshima International University (2006-2007)
Hiroshima University (2005) |
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Principal Investigator |
YAMAOKA Kaoru Hiroshima International University, Faculty of Health Sci, Dept Physical Therapy, Professor (10200586)
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| Co-Investigator(Kenkyū-buntansha) |
HIRAMA Masashiro Tohoku University, Graduate School of Science, Department of Chemistry, Professor (30165203)
YAMASHITA Shuji Tohoku University, Graduate School of Science, Department of Chemistry, Assistant Professor (50419991)
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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 |
¥14,160,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2007: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2006: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2005: ¥4,500,000 (Direct Cost: ¥4,500,000)
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| Keywords | ciguatoxin / sodium channel / structure-function relationship / tetrodotoxin-resistant / nociception / voltage-sensor domain / lipid bilayer membrane / gating mechanism / ビオチン |
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| Research Abstract |
An image of steric structure of ion channels has been illustrated by Mackinnon at al (2003) in the studies of crystal structure of potassium channels. According to them, voltage sensor domains fluctuate voltage-dependently in the lipid bilayer membrane outside of pore domains. Ciguatoxins (Mw is just over 1000) are composed of 13 ether rings (A to M ring), lipid soluble, have relatively rigid structure and selectively activate voltage-dependent sodium channels (VDSC). Theses distinct features of this toxin may well contribute to elucidating steric structure of VDSC by analyzing interaction of ciguatoxins and VDSC. By doing this, we obtained four important results regarding structural information of VDSC. 1. One of the synthesized ciguatoxin, CTX3C selectively acts on domain 2 of 4 membrane-spanning domains of VDSC. 2. Experiments using biotinized CTX3C or 51-OH-CTX3C at B-ring indicated that A or B ring side of the molecule acts as functional group of cigatoxins. 3. Subtle structural changes in F-ring (structural alteration of original 9-membered F-ring to 8 or 10-membered ring) induced important reduction in potency of CTX3C action. 4. CTX3C preferentially modulates tetrodotoxin-resistant pain-sensing sodium channel, Na_<v>1.8, through acting on domain 2 of the molecule over tetrodotoxin-sensitive Na channels, Na_<v>1.2 and Na_<v>1.4. These results indicate importance of domain 2 in the structural studies of VDSC.
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