CaM kinase augments cardiac L-type Ca2+ current:: a cellular mechanism for long Q-T arrhythmias

被引:127
作者
Wu, YJ
MacMillan, LB
McNeill, RB
Colbran, RJ
Anderson, ME
机构
[1] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Med Ctr, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA
[3] Vanderbilt Univ, Med Ctr, Dept Pharmacol, Nashville, TN 37232 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY | 1999年 / 276卷 / 06期
关键词
arrhythmia; calcium channels; action potential; long Q-T syndrome; sarcoplasmic reticulum;
D O I
10.1152/ajpheart.1999.276.6.H2168
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Early afterdepolarizations (EAD) caused by L-type Ca2+ current (I-Ca,I-L) are thought to initiate long Q-T arrhythmias, but the role of intracellular Ca2+ in these arrhythmias is controversial. Rabbit ventricular myocytes were stimulated with a prolonged EAD-containing action potential-clamp waveform to investigate the role of Ca2+/calmodulin-dependent protein kinase II (CaM kinase) in I-Ca,I-L during repolarization. I-Ca,I-L was initially augmented, and augmentation was dependent on Ca2+ from the sarcoplasmic reticulum because the augmentation was prevented by ryanodine or thapsigargin. I-Ca,I-L augmentation was also dependent on CaM kinase, because it was prevented by dialysis with the inhibitor peptide AC3-I and reconstituted by exogenous constitutively active CaM kinase when Ba2+ was substituted for bath Ca2+. Ultrastructural studies confirmed that endogenous CaM kinase, L-type Ca2+ channels, and ryanodine receptors colocalized near T tubules. EAD induction was significantly reduced in current-clamped cells dialyzed with ACS-I (4/15) compared with cells dialyzed with an inactive control peptide (11/15, P = 0.013). These findings support the hypothesis that EADs are facilitated by CaM kinase.
引用
收藏
页码:H2168 / H2178
页数:11
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