Adrenergic regulation of the rapid component of delayed rectifier K+ current: Implications for arrhythmogenesis in LQT2 patients
Adrenergic regulation of the rapid component of delayed rectifier K+ current: Implications for arrhythmogenesis in LQT2 patients
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DOI：
10.1016/j.hrthm.2009.02.045
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发表时间：
2009-07-01
期刊：
影响因子：
5.5
通讯作者：
Horie, Minoru
中科院分区：
文献类型：
--
作者：
Zankov, Dimitar P.;Yoshida, Hidetada;Horie, Minoru
BACKGROUND KCNH2 gene mutations disrupting rapid component of I-K (I-Kr) underlie type 2 congenital long QT syndrome (LQT2). Startled auditory stimuli are specific symptomatic triggers in LQT2, thus suggesting fast arrhythmogenic mechanism.OBJECTIVE We investigated acute alpha(1A)- and cyclic adenosine monophosphate (cAMP)-related beta-adrenergic modulation of I-Kr in HL-1 cardiomyocytes, wild type (WT)- and 2 LQT2-associated mutant Kv11.1 channels (Y43D- and K595E-011.1) reconstituted in Chinese hamster ovary (CHO) cells.METHODS I-Kr and Kv11.1 currents were recorded using the whole-cell patch-damp technique and confocal microscopy of HL-1 cardiomyocytes transfected with green fluorescent protein (GFP)tagged pleckstrin homology domain of phospholipase C-delta(1) visualized fluctuations of membrane phosphatidylinositol 4,5-bisphosphate (PIP2) content.RESULTS In HL-1 cardiomyocytes expressing human alpha(1A)-adrenoceptor, superfusion with phenylephrine significantly reduced I-Kr amplitude, shifted current activation to more positive potentials, and accelerated kinetics of deactivation. Confocal images showed a decline of membrane PIP2 content during phenylephrine exposure. Simultaneous application of adenylyl cyclase activator forskolin and phosphodiesterase inhibitor 3-isobutyt-1-methylxantine (IBMX) shifted I-Kr activation to more negative potentials and decreased tail current amplitudes after depolarizations between +10 and +50 mV. In CHO cells, alpha(1A)-adrenoceptor activation downregutated WT-Kv11.1 channels and forskotin/IBMX produced a dual effect. Expressed atone, the Y43D-Kv11.1 or K595E-Kv11.1 channel had no measurable function. However, co-expression of WT-Kv11.1 and each mutant protein evoked currents with loss-of-function alterations but identical to WT-Kv11.1 alpha(1A)- and forskolin/IBMX-induced regulation.CONCLUSION Acute adrenergic regulation of at least 2 Kv11.1 mutant channels is preserved as in WT-Kv11.1 and native I-Kr. Suppression of alpha(1A)-adrenoceptor-related transduction might have therapeutic implications in some cases of LQT2.
