| Project/Area Number |
18590757
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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 |
Circulatory organs internal medicine
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| Research Institution | Hokkaido University |
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Principal Investigator |
MAKITA Naomasa Hokkaido University, Hokkaido University Hospital, Lecturer (00312356)
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| Co-Investigator(Kenkyū-buntansha) |
MOCHIZUKI Naoki National Cardiovascular Center Research Institute, Department of StructuralAnalysis, Director (30311426)
SHIOJIMA Ichiro Chiba University, Graduate School of Medicine, Associate Professor (90376377)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,950,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2007: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2006: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | Akt / phosphorylation / Na channel / Lethal arrhythmias / リン酸化シグナル / トランスジェニック動物 |
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| Research Abstract |
Akt is a serine-threonine phosphatase implicated in wide variety of signal transductions including cell proliferation and apoptosis. Selective overexpression of Akt in mice heart results in cardiac hypertrophy, but occasionally, some transgenic mice die suddenly with unknown causes before the cardiac hypertrophy is fully established, suggesting life-threatening arrhythmias during Akt-induction. The purpose of the study was to elucidate the biophysical and biochemical mechanisms underlying Akt-induced cardiac hypertrophy and lethal arrhythmias. We focused on cardiac Na channel Navl.5, because Navl.5, unlike other cardiac ion channels, has two Akt phosphorylation recognition sequences (RXRXXT/S). Navl.5 was coexpressed in HEK 293 cells together with Akt or its phosphorylation deficient mutant Akt-3A (K179A+T308A+S478A), and the biophysical properties were determined by whole-cell patch clamp technique. Current density of Nav.15 was significantly increased by Akt but not by Akt-3A. Voltage-dependence of the activation curve, but not inactivation, was significantly shifted in the depolarizing direction. Furthermore, coimmunoprecipitation of FLAG-tagged Nav.15 with anti-phosphorylated-Akt antibodies revealed that Akt but not Akt-3A increased the association of Akt with cardiac Na channel. These results suggest that Akt modified the biophysical properties and expression levels of Na channel, leading to induce of lethal arrhythmias. Further study including in vivo ECG recording in Aid transgenic mice are required to elucidate the mechanistic link between cardiac Akt signaling pathway and the lethal arrhythmias.
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