Intrinsic mechanisms of the ion channels associated with life threatening arrhythmia
| Project/Area Number |
17590194
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
General physiology
|
|---|
| Research Institution | University of Occupational and Environmental Health, Japan |
|---|
Principal Investigator |
NAGATOMO Toshihisa University of Occupational and Environmental Health, Japan, University Hospital, Associate Professor (50258604)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
ABE Haruhiko University of Occupational&Environmental Health, Japan, School of Medicine, Lecturer (70231967)
|
|---|
| Project Period (FY) |
2005 – 2007
|
| Project Status |
Completed (Fiscal Year 2007)
|
| Budget Amount *help |
¥3,730,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥330,000)
Fiscal Year 2007: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2006: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000)
|
|---|
| Keywords | Electrophysiology / long QT syndrome / Sodium channel / Potassium channel / hERG channel / Gene / Protein trafficking / Signal transduction / 生理学 / 循環器・高血圧 |
|---|
| Research Abstract |
1. Congenital long QT syndrome (Na^+ channel mutation)
Type 3 of the long QT syndrome (LQT3) is caused by mutations in SCN5A, the gene that encodes the α-subunit of the human voltage-dependent cardiac Na^+ channel. Previous functional studies of SCN5A mutants indicated that most LQT3 mutations cause increased late sodium current (I_<Na>). Ventricular tachyarrhythmias and sudden cardiac death in patients with LQT3 tend to occur during sleep or at rest when the heart rate is slow. However, the intrinsic mechanism (s) that might explain why arrhythmia attack is most prevalent at slower heart rates has not been investigated. The intrinsic kinetic property of the I^<Na> in the LQT3 R1623Q mutant, preferential rate-dependent reduction of phase 3 'Na under non-equilibrium condition, accounted for the enhanced shortening of QT interval at faster heart rates. On the other hand, β-adrenergic agents were ineffective in reducing the late I_<Na>. Different intrinsic mechanisms are involved in QT int
… More
erval shortening induced by pacing and ii-adrenergic stimulation. The mechanism of QT shortening by overdrive pacing might mainly include a frequency-dependent reduction of the late and phase 3 I_<Na> in R1623Q mutant channels, while a balance of inward and outward currents might explain the QT interval shortening by β-adrenergic stimulation.
2. Acquired long QT syndrome (Cardiac hERG K^+ channel)
Many drugs associated with acquired long QT syndrome (LQTS) directly block human ether-a-go-go-related gene (hERG) cardiac K+ channels. Recently, disrupted trafficking of the hERG channel protein was proposed as a new mechanism underlying LQTS, but whether this defect coexists with the hERG current block remains unclear. This study investigated how ketoconazole, a direct hERG current inhibitor, affects the trafficking of hERG channel protein. Therapeutic ketoconazole caused acquired LQTS by direct blocking of the hERG channel current and by disrupting hERG protein trafficking. Common drug-binding sites (Y652, F656) were involved in the direct hERG channel block, but not in the hERG trafficking defect. These findings should be considered when evaluating new drugs. Less
|
Report
(4 results)
Research Products
(21 results)
-
-
[Journal Article] Coexistence of hERO current block and disruption of protein trafficking in ketoconazole-induced long QT syndrome.2008
Author(s)
Takemasa H, Nagatomo T, Abe H, Kawakami K, Igarashi T, Tsurugi T, Kabashima N, Tamura M, Okazaki M, Delisle BP, January CT, Otsuji Y
-
Journal Title
Br J Pharmacol 153
Pages: 439-447
Description
「研究成果報告書概要(欧文)」より
Related Report
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
