The role of Hsp70 in quality control of mutant hERG protein associated LQT2 and its therapeutic application.

2015 Fiscal Year Final Research Report

• Project/Area Number: 25461109
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Tottori University
• Principal Investigator: Li Peili 鳥取大学, 医学(系)研究科(研究院), 助教 (40464292)
• Co-Investigator(Kenkyū-buntansha): Shirayoshi Yasuaki 鳥取大学, 医学系研究科, 准教授 (90249946)
• Co-Investigator(Renkei-kenkyūsha): Ikeda Nobuhito 鳥取大学, 医学系研究科, 助教 (50620316)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: LQT2 / hERG / histone deacetylase 6 / acetylation / ubiquitination / lysine

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.

Free Research Field

循環器内科学