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| 題名: | PP2 Prevents beta-Adrenergic Stimulation of Cardiac Pacemaker Activity |
| 作者: | Huang, Jianying
Lin, Yen-Chang
Hileman, Stan
Martin, Karen H.
Hull, Robert
Yu, Han-Gang |
| 貢獻者: | 生物科技研究所 |
| 關鍵詞: | Src tyrosine kinases
tyrosine phosphorylation
cAMP;beta-adrenergic stimulation
pacemaker current I-f
HCN4 channel internalization
sinus node |
| 日期: | 2014-06 |
| 上傳時間: | 2015-01-26 10:18:05 (UTC+8) |
| 摘要: | One of the main strategies for cancer therapy is to use tyrosine kinase inhibitors for inhibiting tumor proliferation. Increasing evidence has demonstrated the potential risks of cardiac arrhythmias (such as prolonged QT interval) of these drugs. We report here that a widely used selective inhibitor of Src tyrosine kinases, 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d] pyrimidine (PP2), can inhibit and prevent beta-adrenergic stimulation of cardiac pacemaker activity. First, in dissected rat sinus node, PP2 inhibited and prevented the isoproterenol-induced increase of spontaneous beating rate. Second, in isolated rat sinus node myocytes, PP2 suppressed the hyperpolarization-activated "funny" current (traditionally called cardiac pacemaker current, If) by negatively shifting the activation curve and decelerating activation kinetics. Third, in isolated rat sinus node myocytes, PP2 decreased the Src kinase activity, the cell surface expression, and tyrosine phosphorylation of hyperpolarization-activated, cyclic nucleotide-modulated channel 4 (HCN4) channel proteins. Finally, in human embryonic kidney 293 cells overexpressing recombinant human HCN4 channels, PP2 reversed the enhancement of HCN4 channels by isoproterenol and inhibited 573x, a cyclic adeno-sine momophosphate-insensitive human HCN4 mutant. These results demonstrated that inhibition of Src kinase activity in heart by PP2 decreased and prevented b-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 main channel protein that controls the heart rate. |
| 關聯: | JOURNAL OF CARDIOVASCULAR PHARMACOLOGY 卷: 63 期: 6 頁碼: 533-543 |
| 顯示於類別: | [生物科技研究所 ] 期刊論文
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