| Project/Area Number |
25461109
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Cardiovascular medicine
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| Research Institution | Tottori University |
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Principal Investigator |
Li Peili 鳥取大学, 医学(系)研究科(研究院), 助教 (40464292)
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| Co-Investigator(Kenkyū-buntansha) |
Shirayoshi Yasuaki 鳥取大学, 医学系研究科, 准教授 (90249946)
池田 信人 鳥取大学, 医学(系)研究科(研究院), 助教 (50620316)
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| Co-Investigator(Renkei-kenkyūsha) |
Ikeda Nobuhito 鳥取大学, 医学系研究科, 助教 (50620316)
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| Project Period (FY) |
2013-04-01 – 2016-03-31
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| Project Status |
Completed (Fiscal Year 2015)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Keywords | LQT2 / hERG / histone deacetylase 6 / acetylation / ubiquitination / lysine / 変異hERG / アセチル化 / ユビキチン化 / HDAC6 / HDAC阻害剤 / histone deacetylase / mutation / mutant hERG / histine deacetylase / Histone deacetylase 6 / histone deacetylase 10 / chaperone / protein quality control |
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| Outline of Final Research Achievements |
LQT2 results from the mutations in hERG causing reduced hERG protein expression on cell membrane and hERG currents. We found a novel role of histone deacetylase (HDAC) 6 in hERG. Three HDAC pan-inhibitors, a HDAC6 selective inhibitor (TBA) or knockdown of HDAC6 increased wild-type (WT) protein expression and induced two mutant hERGs’ maturation with enhanced the acetylation of hERG protein, whereas, decreased the ubiquitin with prolonged half-life. Co-expression of HDAC6 posed opposite effects on hERG. Immunochemistry and electrophysiological studies confirmed the results. Substitutions of the three lysine residues (116, 495 and 757) with arginine in hERG erased the effects of HDAC6 on hERG protein level, acetylation and ubiquitintation levels, respectively. TBA treatment enhanced the expression of ERG in mouse cardiomyocytes HL-1, increased IKr and shortened action potential duration. The results indicate HDAC6 regulates hERG by altering acetylation/ubiquitination of hERG proteins.
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