文化大學機構典藏 CCUR:Item 987654321/30781
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    jsp.display-item.identifier=請使用永久網址來引用或連結此文件: https://irlib.pccu.edu.tw/handle/987654321/30781


    题名: PP2 Prevents Isoproterenol Stimulation of Cardiac Pacemaker Activity
    作者: Huang, Jianying
    Lin, Yen-Chang
    Hileman, Stan
    Martin, Karen H.
    Hull, Robert
    Yu, Han-Gang
    贡献者: Grad Inst Biotechnol
    关键词: PP2
    isoproterenol
    Src tyrosine kinases
    tyrosine phosphorylation
    pacemaker current i(f)
    HCN4
    sinus node
    日期: 2015-02
    上传时间: 2015-10-30 14:46:18 (UTC+8)
    摘要: Increasing evidence has demonstrated the potential risks of cardiac arrhythmias (such as prolonged QT interval) using tyrosine kinase inhibitors for cancer therapy. We report here that a widely used selective inhibitor of Src tyrosine kinases, PP2, can inhibit and prevent isoproterenol stimulation of cardiac pacemaker activity. In dissected rat sinus node, PP2 inhibited and prevented isoproterenol stimulation of spontaneous beating rate. In isolated sinus node myocytes, PP2 suppressed the hyperpolarization-activated "funny" current (I-f) by negatively shifting the activation curve and decelerating activation kinetics, associated with decreased cell surface expression and reduced tyrosine phosphorylation of hyperpolarization-activated cyclic nucleotide-modulated channel 4 (HCN4) channel proteins. In human embryonic kidney 293 cells overexpressing recombinant human HCN4 channels, PP2 reversed isoproterenol stimulation of HCN4 and inhibited HCN4-573x, a cAMP-insensitive human HCN4 mutant. Isoprotenrenol had little effects on HCN4-573x. These results demonstrated that inhibition of presumably tyrosine Src kinase activity in heart by PP2 decreased and prevented the potential beta-adrenergic stimulation of cardiac pacemaker activity. These effects are mediated, at least partially, by a cAMP-independent attenuation of channel activity and cell surface expression of HCN4, the key channel protein that controls the heart rate.
    關聯: JOURNAL OF CARDIOVASCULAR PHARMACOLOGY 卷: 65 期: 2 頁碼: 193-202
    显示于类别:[生物科技研究所 ] 期刊論文

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