Molecular mechanism underlying the gating regulation of Ca^<2+> permeable channel via Ca^<2+> complex
| Project/Area Number |
16590043
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Biological pharmacy
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| Research Institution | Toho University (2005)
The University of Tokyo (2004) |
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Principal Investigator |
ADACHI Satomi Toho University, Faculty of Medicine, Department of Pharmacology, Associate Professor, 医学部, 助教授 (00184185)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2004: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | calcium channel / calcium / channel / signal / protein-protein interaction / cardiac muscle / atrial muscle / calcium antagonist / シグナル伝達 / 発生・分化 / 不整脈 / 薬理学 / 循環器・高血圧 / 細胞骨格 / カルシウムシグナル / 心筋細胞 |
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| Research Abstract |
L-type Ca^<2+> channel serves as a primary step in the regulation of Ca^<2+> signaling. In this project, we aimed at clarifying the molecular mechanism underlying the gating regulation of L-type Ca^<2+> channel α_<1C> subunit (Ca_v1.2) through the following approaches :
1)Clarification of signaling molecular complex associated with L-type Ca^<2+> channel α_<1C> subunit (Ca_v1.2) :
We screened proteins associated with the carboxyl terminus of Ca_v1.2 in the cDNA library of mouse embryo (E11.5) with yeast two-hybrid screening method. We found that the C-terminus of Ca_v1.2 interacts with phosphatidylcholine transfer protein-like protein (PCTP-L/STARD10). Northern blot and Western blot analysis revealed that PCTP-L was expressed in liver, kidney, and testis as well as in embryonic heart and, in adult rodent hearts, in atria but not in ventricle. PCTP-L colocalized and was coimmunoprecipitated with Ca_v1.2 in rat atria. When PCTP-L was coexpressed with Ca_v1.2, in BHK6 cells, PCTP-L facilita
… More
ted Ca_v1.2 via the alteration of the inactivation mechanism through the specific interaction with Ca_v1.2. The knockdown of PCTP-L in neonatal atrial myocytes by RNAi resulted in the shortening of the plateau phase of action potentials and an increase in the frequency of spontaneous Ca^<2+> transients. These results are attributed, in a part, to the down-regulation of the activity of the L-type Ca^<2+> channel as a result of the relief of the facilitatory modulation by PCTP-L.
2)Functional analysis of structural topology of amino acids around Ca^<2+> selective pore region of Ca_v1.2 :
We analyzed the topology of amino acids in the pore forming IIIS5-S6 linker region of Ca_v1.2, including Phe^<1112> and Ser^<1115> that are critical for DHP binding, with substituted cysteine accessibility method. The accessibility of cysteine-substituted amino acids from hydrophilic pathway was assed as the block of Ca^<2+> channel current by MTSET. We found that Phe^<1112> is exposed to hydrophilic environment at depolarized condition, while Ser^<1115> appears to be buried in hydrophobic environment, thus suggesting that the voltage-dependent conformational change around Phe^<1112> may be responsible for the voltage-dependent change of the binding affinity of DHP to the Ca^<2+> channel, which is in good agreement with our previous homology model of the DHP binding pocket of Ca_v1.2. Less
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Report
(3 results)
Research Products
(23 results)
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[Journal Article] Compounds structurally related to tamoxifen as openers of large-conductance calcium-activated K^+ channel.2005
Author(s)
Sha, Y., Tashima, T., Mochizuki, Y., Toriumi, Y., Adachi-Akahane, S., Nonomura, T., Cheng, M., Ohwada, T.
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Journal Title
Chem.Pharm.Bull. 53(10)
Pages: 1372-1373
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Genetic polymorphisms and haplotypes of the human cardiac sodium channel alpha subunit gene (SCN5A) in Japanese and their association with arrhythmia.2005
Author(s)
Maekawa, K., Saito, Y., Ozawa, S., Adachi-Akahane, S., Kawamoto, M., Komamura, K., Shimizu, W., Ueno, K., Kamakura, S., Kamatani, N., Kitakaze, M., Sawada, J.
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Journal Title
Ann.Hum.Genet. 69(4)
Pages: 413-428
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Solution structure of ADO1, a toxin extracted from the saliva of the assassin bug, Agriosphodrus dohrni.2004
Author(s)
Bernard, C., Corzo, G, Adachi-Akahane, S., Foures, G., Kanemaru, K., Furukawa, Y, Nakajima, T., Darbon, H.
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Journal Title
PROTEINS: Structure, Function, and Bioinformatics 54(2)
Pages: 195-205
Description
「研究成果報告書概要(欧文)」より
Related Report
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