Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI 48108, USA.
FASEB J. 2012 Jan;26(1):63-72. doi: 10.1096/fj.10-179770. Epub 2011 Sep 24.
Evidence supports the expression of brain-type sodium channels in the heart. Their functional role, however, remains controversial. We used global Na(V)1.6-null mice to test the hypothesis that Na(V)1.6 contributes to the maintenance of propagation in the myocardium and to excitation-contraction (EC) coupling. We demonstrated expression of transcripts encoding full-length Na(V)1.6 in isolated ventricular myocytes and confirmed the striated pattern of Na(V)1.6 fluorescence in myocytes. On the ECG, the PR and QRS intervals were prolonged in the null mice, and the Ca(2+) transients were longer in the null cells. Under patch clamping, at holding potential (HP) = -120 mV, the peak I(Na) was similar in both phenotypes. However, at HP = -70 mV, the peak I(Na) was smaller in the nulls. In optical mapping, at 4 mM K(+), 17 null hearts showed slight (7%) reduction of ventricular conduction velocity (CV) compared to 16 wild-type hearts. At 12 mM K(+), CV was 25% slower in a subset of 9 null vs. 9 wild-type hearts. These results highlight the importance of neuronal sodium channels in the heart, whereby Na(V)1.6 participates in EC coupling, and represents an intrinsic depolarizing reserve that contributes to excitation.
证据支持脑型钠通道在心脏中的表达。然而，其功能作用仍存在争议。我们使用全球 Na(V)1.6 基因敲除小鼠来验证假说，即 Na(V)1.6 有助于维持心肌的传播和兴奋-收缩（EC）偶联。我们证明了编码全长 Na(V)1.6 的转录本在分离的心室肌细胞中的表达，并证实了 Na(V)1.6 荧光在肌细胞中的条纹状模式。在心电图上，Na(V)1.6 基因敲除小鼠的 PR 和 QRS 间隔延长，而 Na(V)1.6 基因敲除细胞的 Ca(2+)瞬变更长。在膜片钳实验中，在保持电位（HP）=-120 mV 时，两种表型的峰值 I(Na)相似。然而，在 HP=-70 mV 时，Na(V)1.6 基因敲除细胞的峰值 I(Na)较小。在光学映射中，在 4 mM K(+)下，17 只 Na(V)1.6 基因敲除小鼠的心室传导速度（CV）比 16 只野生型小鼠轻微（7%）降低。在 12 mM K(+)下，9 只 Na(V)1.6 基因敲除小鼠中的一部分 CV 比 9 只野生型小鼠慢 25%。这些结果强调了神经元钠通道在心脏中的重要性，其中 Na(V)1.6 参与 EC 偶联，并代表有助于兴奋的内在去极化储备。
