Differential modulation of late sodium current by protein kinase A in R1623Q mutant of LQT3.
Differential modulation of late sodium current by protein kinase A in R1623Q mutant of LQT3.
复制标题
LQT3 R1623Q 突变体中蛋白激酶 A 对晚钠电流的差异调节。
DOI：
10.1016/j.lfs.2009.01.001
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发表时间：
2009
期刊：
影响因子：
6.1
通讯作者：
Otsuji,Yutaka
中科院分区：
文献类型：
--
作者：
Tsurugi,Takuo;Nagatomo,Toshihisa;Abe,Haruhiko;Oginosawa,Yasushi;Takemasa,Hiroko;Kohno,Ritsuko;Makita,Naomasa;Makielski,JonathanC;Otsuji,Yutaka
目的在3型长QT综合征（LQT3）中，通过双极起搏缩短QT间期用于预防危及生命的心律失常。然而，目前尚不清楚β-肾上腺素能药物诱导的心率加快是否对晚钠电流（INa）产生与起搏治疗相似的影响。主要方法将编码野生型（WT）和R1623Q突变型hNav1.5的cDNA稳定转染HEK293细胞，观察蛋白激酶A（PKA）和氟化物对INain R1623Q突变型通道的β-肾上腺素样作用。在R1623 Q通道中，2 mM pCPT-AMP和120 mM氟化物显著延迟宏观电流衰减，并以时间依赖性方式增加晚期I Na的相对幅度。在WT和R1623Q通道中，氟化物对峰值INagating动力学（激活、失活、从失活中恢复）的调节相似。氟的影响几乎完全取消伴随透析与蛋白激酶抑制剂。我们还比较了起搏和β-肾上腺素能刺激对迟发性INa的频率依赖性。氟增强了频率依赖性的降低晚INa，这是由于优先延迟恢复晚INa。然而，在稳态时，晚INaby氟的增加比晚INa的频率依赖性减少更有效。意义不同的基本机制参与了起搏和β-肾上腺素能刺激在LQT3中QT间期缩短。
AIMSIn the type 3 long QT syndrome (LQT3), shortening of the QT interval by overdrive pacing is used to prevent life-threatening arrhythmias. However, it is unclear whether accelerated heart rate induced by β-adrenergic agents produces similar effects on the late sodium current (INa) to those by overdrive pacing therapy. We analyzed the β-adrenergic-like effects of protein kinase A and fluoride on INain R1623Q mutant channels.MAIN METHODScDNA encoding either wild-type (WT) or R1623Q mutant of hNav1.5 was stably transfected into HEK293 cells. INawas recorded using a whole-cell patch-clamp technique at 23 °C.KEY FINDINGSIn R1623Q channels, 2 mM pCPT-AMP and 120 mM fluoride significantly delayed macroscopic current decay and increased relative amplitude of the late INain a time-dependent manner. Modulations of peak INagating kinetics (activation, inactivation, recovery from inactivation) by fluoride were similar in WT and R1623Q channels. The effects of fluoride were almost completely abolished by concomitant dialysis with a protein kinase inhibitor. We also compared the effect of pacing with that of β-adrenergic stimulation by analyzing the frequency-dependence of the late INa. Fluoride augmented frequency-dependent reduction of the late INa, which was due to preferential delay of recovery of late INa. However, the increase in late INaby fluoride at steady-state was more potent than the frequency-dependent reduction of late INa.SIGNIFICANCEDifferent basic mechanisms participate in the QT interval shortening by pacing and β-adrenergic stimulation in the LQT3.