Zhang Xiao-Dong, Timofeyev Valeriy, Li Ning, Myers Richard E, Zhang Dai-Min, Singapuri Anil, Lau Victor C, Bond Chris T, Adelman John, Lieu Deborah K, Chiamvimonvat Nipavan
Division of Cardiovascular Medicine, University of California, Davis, One Shields Avenue, GBSF 6315, Davis, CA 95616, USA.
Cardiovasc Res. 2014 Feb 1;101(2):317-25. doi: 10.1093/cvr/cvt262. Epub 2013 Nov 26.
Small conductance Ca(2+)-activated K(+) channels (K(Ca)2 or SK channels) have been reported in excitable cells, where they aid in integrating changes in intracellular Ca(2+) (Ca(i)²⁺) with membrane potentials. We have recently reported the functional expression of SK channels in human and mouse cardiac myocytes. Additionally, we have found that the channel is highly expressed in atria compared with the ventricular myocytes. We demonstrated that human cardiac myocytes expressed all three members of SK channels (SK1, 2, and 3); moreover, the different members are capable of forming heteromultimers. Here, we directly tested the contribution of SK3 to the overall repolarization of atrial action potentials.
We took advantage of a mouse model with site-specific insertion of a tetracycline-based genetic switch in the 5' untranslated region of the KCNN3 (SK3 channel) gene (SK3(T/T)). The gene-targeted animals overexpress the SK3 channel without interfering with the normal profile of SK3 expression. Whole-cell, patch-clamp techniques show a significant shortening of the action potential duration mainly at 90% repolarization (APD90) in atrial myocytes from the homozygous SK3(T/T) animals. Conversely, treatment with dietary doxycycline results in a significant prolongation of APD90 in atrial myocytes from SK3(T/T) animals. We further demonstrate that the shortening of APDs in SK3 overexpression mice predisposes the animals to inducible atrial arrhythmias.
SK3 channel contributes importantly towards atrial action potential repolarization. Our data suggest the important role of the SK3 isoform in atrial myocytes.
小电导钙激活钾通道（K（Ca）2或SK通道）已在可兴奋细胞中被报道，在这些细胞中它们有助于将细胞内钙（Ca（i）²⁺）的变化与膜电位整合起来。我们最近报道了SK通道在人和小鼠心肌细胞中的功能性表达。此外，我们发现与心室肌细胞相比，该通道在心房中高度表达。我们证明人类心肌细胞表达SK通道的所有三个成员（SK1、2和3）；此外，不同成员能够形成异源多聚体。在这里，我们直接测试了SK3对心房动作电位整体复极化的贡献。
我们利用了一种小鼠模型，该模型在KCNN3（SK3通道）基因的5'非翻译区位点特异性插入了基于四环素的基因开关（SK3（T/T））。基因靶向动物过度表达SK3通道而不干扰SK3表达的正常模式。全细胞膜片钳技术显示，纯合SK3（T/T）动物心房肌细胞的动作电位持续时间主要在90%复极化（APD90）时显著缩短。相反，用饮食中的强力霉素处理会导致SK3（T/T）动物心房肌细胞的APD90显著延长。我们进一步证明，SK3过表达小鼠中APD的缩短使动物易诱发房性心律失常。
SK3通道对心房动作电位复极化起重要作用。我们的数据表明SK3亚型在心房肌细胞中的重要作用。
