Cyclic AMP regulates the HERG K+ channel by dual pathways

被引:135
|
作者
Cui, J
Melman, Y
Palma, E
Fishman, GI
McDonald, TV [1 ]
机构
[1] Albert Einstein Coll Med, Dept Med, Sect Mol Cardiol, Bronx, NY 10461 USA
[2] Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA
[3] Mt Sinai Sch Med, Zena & Michael A Wiener Cardiovasc Inst, Sect Myocardial Biol, Dept Med, New York, NY 10029 USA
[4] Mt Sinai Sch Med, Zena & Michael A Wiener Cardiovasc Inst, Sect Myocardial Biol, Dept Physiol & Biophys, New York, NY 10029 USA
[5] Mt Sinai Sch Med, Zena & Michael A Wiener Cardiovasc Inst, Sect Myocardial Biol, Dept Biochem, New York, NY 10029 USA
[6] Mt Sinai Sch Med, Zena & Michael A Wiener Cardiovasc Inst, Sect Myocardial Biol, Dept Mol Biol, New York, NY 10029 USA
关键词
D O I
10.1016/S0960-9822(00)00516-9
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Lethal cardiac arrhythmias are a hallmark of the hereditary Long QT syndrome (LQTS), a disease produced by mutations of cardiac ion channels [1], Often these arrhythmias are stress-induced, suggesting a relationship between (-beta)adrenergic activation of adenylate cyclase and cAMP-dependent alteration of one or more of the ion channels involved in LOTS, Second messengers modulate ion channel activity either by direct interaction or through intermediary kinases and phosphatases. Here we show that the second messenger cAMP regulates the K+ channel mutated in the LQT2 form of LOTS, HERG [2], both directly and indirectly. Activation of cAMP-dependent protein kinase (PKA) causes phosphorylation of HERG accompanied by a rapid reduction in current amplitude, acceleration of voltage-dependent deactivation, and depolarizing shift in voltage-dependent activation. In a parallel pathway, cAMP directly binds to the HERG protein with the opposing effect of a hyperpolarizing shift in voltage-dependent activation. The summation of cAMP-mediated effects is a net diminution of the effective current, but when HERG is complexed with with the K+ channel accessory proteins MiRP1 or minK, the stimulatory effects of cAMP are favored. These findings provide a direct link between stress and arrhythmia by a unique mechanism where a single second messenger exerts complex regulation of an ion channel via two distinct pathways.
引用
收藏
页码:671 / 674
页数:4
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