Rossow Charles F, Dilly Keith W, Santana Luis F
Department of Physiology and Biophysics, University of Washington, Seattle, WA 98118, USA.
Circ Res. 2006 May 26;98(10):1306-13. doi: 10.1161/01.RES.0000222028.92993.10. Epub 2006 Apr 13.
Kv4 channels are differentially expressed across the mouse left ventricular free wall. Accordingly, the transient outward K+ current (Ito), which is produced by Kv4 channels, is greater in left ventricular epicardial (EPI) than in endocardial (ENDO) cells. However, the mechanisms underlying heterogeneous Kv4 expression in the heart are unclear. Here, we tested the hypothesis that differential [Ca2+]i and calcineurin/NFATc3 signaling in EPI and ENDO cells contributes to the gradient of Ito function in the mouse left ventricle. In support of this hypothesis, we found that [Ca2+]i, calcineurin, and NFAT activity were greater in ENDO than in EPI myocytes. However, the amplitude of Ito was the same in ENDO and EPI cells when [Ca2+]i, calcineurin, and NFAT activity were equalized. Consistent with this, we observed complete loss of Ito and Kv4 heterogeneity in NFATc3-null mice. Interestingly, Kv4.3, Kv4.2, and KChIP2 genes had different apparent thresholds for NFATc3-dependent suppression and were ordered as Kv4.3 approximately KChIP2>Kv4.2. Based on these data, we conclude that calcineurin and NFATc3 constitute a Ca(2+)-driven signaling module that contributes to the nonuniform distribution of Kv4 expression, and hence Ito function, in the mouse left ventricle.
Kv4通道在小鼠左心室游离壁上呈差异表达。因此，由Kv4通道产生的瞬时外向钾电流（Ito）在左心室心外膜（EPI）细胞中比在心内膜（ENDO）细胞中更大。然而，心脏中Kv4表达异质性的潜在机制尚不清楚。在此，我们检验了以下假设：EPI和ENDO细胞中不同的细胞内钙离子浓度（[Ca2+]i）以及钙调神经磷酸酶/活化T细胞核因子c3（calcineurin/NFATc3）信号传导促成了小鼠左心室Ito功能的梯度差异。为支持这一假设，我们发现ENDO心肌细胞中的[Ca2+]i、钙调神经磷酸酶和NFAT活性比EPI心肌细胞中的更高。然而，当[Ca2+]i、钙调神经磷酸酶和NFAT活性达到平衡时，ENDO和EPI细胞中Ito的幅度是相同的。与此一致的是，我们在NFATc3基因敲除小鼠中观察到Ito和Kv4异质性完全丧失。有趣的是，Kv4.3、Kv4.2和钾通道相互作用蛋白2（KChIP2）基因对NFATc3依赖性抑制具有不同的表观阈值，其顺序为Kv4.3≈KChIP2>Kv4.2。基于这些数据，我们得出结论：钙调神经磷酸酶和NFATc3构成了一个由钙离子驱动的信号传导模块，该模块促成了Kv4表达在小鼠左心室中的非均匀分布，进而促成了Ito功能的非均匀分布。
