Accessory kvβ1 subunits differentially modulate the functional expression of voltage-gated K+ channels in mouse ventricular myocytes
Accessory kvβ1 subunits differentially modulate the functional expression of voltage-gated K+ channels in mouse ventricular myocytes
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DOI：
10.1161/01.res.0000156890.25876.63
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发表时间：
2005-03-04
影响因子：
20.1
通讯作者：
Nerbonne, JM
中科院分区：
文献类型：
--
作者：
Aimond, F;Kwak, SP;Nerbonne, JM
电压门控 K+ (Kv) 通道辅助 (β) 亚基与成孔 Kv α 亚基相关，并改变异源表达系统中 Kv 通道的特性和/或细胞表面表达。然而，目前对于 Kv β 亚基在天然心脏 Kv 通道生成中的功能作用知之甚少。利用靶向破坏 Kvbeta(1) 基因 (Kvbeta(1)(-/-)) 的小鼠，进行研究以直接探索 Kvbeta(1) 在心室 Kv 电流生成中的作用。从 Kvbeta(1)(-/-) 和野生型 (WT) 动物的左心室心尖 (LVA) 分离的肌细胞中，动作电位波形和峰值 Kv 电流密度无法区分。然而，对 Kv 电流波形的分析表明，Kvbeta(1)(-/-) (21.0+/-0.9 pA/pF；n=68) 中的平均值+/-SEM I-to,I-f 密度显着低于 (P 小于或等于 0.01)，而 WT (25.3+/-1.4 pA/pF；n=42)、LVA 肌细胞的平均值+/-SEM I-K,I-slow 密度显着较低。 LVA 细胞与 WT (15.9+/-0.7 pA/pF; n=42) 相比，Kvbeta(1)(-/-) (19.1+/-0.9 pA/pF; n=68) 更高 (P 小于或等于 0.01)。药理学研究表明，Kvbeta(1)(-/-) LVA 肌细胞中 I-K,I-slow、I-K,I-slow2 的 TEA 敏感成分选择性增加。与 I-to,I-f 和 I-K,I-slow2 密度的变化平行，Kvbeta(1)(-/-) 心室中 Kv4.3 表达减少，Kv2.1 表达增加。综上所述，这些结果表明 Kvbeta(1) 差异调节心肌 I-to、I-f 和 I-K、I-slow2 通道的功能细胞表面表达。
Voltage-gated K+ (Kv) channel accessory (beta) subunits associate with pore-forming Kv alpha subunits and modify the properties and/or cell surface expression of Kv channels in heterologous expression systems. There is very little presently known, however, about the functional role(s) of Kv beta subunits in the generation of native cardiac Kv channels. Exploiting mice with a targeted disruption of the Kvbeta(1) gene (Kvbeta(1)(-/-)), the studies here were undertaken to explore directly the role of Kvbeta(1) in the generation of ventricular Kv currents. Action potential waveforms and peak Kv current densities are indistinguishable in myocytes isolated from the left ventricular apex (LVA) of Kvbeta(1)(-/-) and wild-type (WT) animals. Analysis of Kv current waveforms, however, revealed that mean+/-SEM I-to,I-f density is significantly (Pless than or equal to0.01) lower in Kvbeta(1)(-/-) (21.0+/-0.9 pA/pF; n=68), than in WT (25.3+/-1.4 pA/pF; n=42), LVA myocytes, and that mean+/-SEM I-K,I-slow density is significantly (Pless than or equal to0.01) higher in Kvbeta(1)(-/-) (19.1+/-0.9 pA/pF; n=68), compared with WT (15.9+/-0.7 pA/pF; n=42), LVA cells. Pharmacological studies demonstrated that the TEA-sensitive component of I-K,I-slow, I-K,I-slow2, is selectively increased in Kvbeta(1)(-/-) LVA myocytes. In parallel with the alterations in I-to,I-f and I-K,I-slow2 densities, Kv4.3 expression is decreased and Kv2.1 expression is increased in Kvbeta(1)(-/-) ventricles. Taken together, these results demonstrate that Kvbeta(1) differentially regulates the functional cell surface expression of myocardial I-to,I-f and I-K,I-slow2 channels.