Chauhan V S, Tuvia S, Buhusi M, Bennett V, Grant A O
Division of Cardiology, Duke University Medical Center, Durham, NC 27710-3504, USA.
Circ Res. 2000 Mar 3;86(4):441-7. doi: 10.1161/01.res.86.4.441.
The cytoskeleton of the cardiomyocyte has been shown to modulate ion channel function. Cytoskeletal disruption in vitro alters Na(+) channel kinetics, producing a late Na(+) current that can prolong repolarization. This study describes the properties of the cardiac Na(+) channel and cardiac repolarization in neonatal mice lacking ankyrin(B), a cytoskeletal "adaptor" protein. Using whole-cell voltage clamp techniques, I(Na) density was lower in ankyrin(B)(-/-) ventricular myocytes than in wild-type (WT) myocytes (-307+/-26 versus -444+/-39 pA/pF, P<0.01). Ankyrin(B)(-/-) myocytes exhibited a hyperpolarizing shift in activation and inactivation kinetics compared with WT. Slower recovery from inactivation contributed to the negative shift in steady-state inactivation in ankyrin(B)(-/-). Single Na(+) channel mean open time was longer in ankyrin(B)(-/-) versus WT at test potentials (V(t)) of -40 mV (1.0+/-0.1 versus 0. 61+/-0.04 ms, P<0.05) and -50 mV (0.8+/-0.1 versus 0.39+/-0.05 ms, P<0.05). Ankyrin(B)(-/-) exhibited late single-channel openings at V(t) -40 and -50 mV, which were not seen in WT. Late I(Na) contributed to longer action potential durations measured at 90% repolarization (APD(90)) at 1 Hz stimulation in ankyrin(B)(-/-) compared with WT (354+/-26 versus 274+/-22 ms, P<0.05). From ECG recordings of neonatal mice, heart rates were slower in ankyrin(B)(-/-) than in WT (380+/-14 versus 434+/-13 bpm, P<0.01). Although the QT interval was similar in ankyrin(B)(-/-) and WT at physiological heart rates, QT-interval prolongation in response to heart rate deceleration was greater in ankyrin(B)(-/-). In conclusion, Na(+) channels in ankyrin(B)(-/-) display reduced I(Na) density and abnormal kinetics at the whole-cell and single-channel level that contribute to prolonged APD(90) and abnormal QT-rate adaptation.
心肌细胞的细胞骨架已被证明可调节离子通道功能。体外细胞骨架破坏会改变钠通道动力学，产生可延长复极化的晚钠电流。本研究描述了缺乏锚蛋白B（一种细胞骨架“衔接”蛋白）的新生小鼠心脏钠通道的特性和心脏复极化情况。使用全细胞电压钳技术，锚蛋白B基因敲除（ankyrin(B)(-/-)）的心室肌细胞中的钠电流（I(Na)）密度低于野生型（WT）肌细胞（-307±26对-444±39 pA/pF，P<0.01）。与WT相比，ankyrin(B)(-/-)肌细胞在激活和失活动力学方面表现出超极化偏移。失活后恢复较慢导致ankyrin(B)(-/-)稳态失活出现负向偏移。在测试电位（V(t)）为-40 mV（1.0±0.1对0.61±0.04 ms，P<0.05）和-50 mV（0.8±0.1对0.39±0.05 ms，P<0.05）时，ankyrin(B)(-/-)的单个钠通道平均开放时间比WT长。ankyrin(B)(-/-)在V(t)为-40和-50 mV时出现晚单通道开放，而WT中未观察到。与WT相比，ankyrin(B)(-/-)在1 Hz刺激下90%复极化时测量的动作电位时程（APD(90)）更长，晚钠电流（Late I(Na)）对此有影响（354±26对274±22 ms，P<0.05）。从新生小鼠的心电图记录来看，ankyrin(B)(-/-)的心率比WT慢（380±14对434±13次/分钟，P<0.01）。虽然在生理心率下ankyrin(B)(-/-)和WT的QT间期相似，但ankyrin(B)(-/-)对心率减慢的反应中QT间期延长更明显。总之，ankyrin(B)(-/-)中的钠通道在全细胞和单通道水平上表现出I(Na)密度降低和异常动力学，这导致APD(90)延长和异常的QT-心率适应性。
