Emerging evidence has demonstrated that nucleoporins (Nups) play a pivotal role in cell-type-specific gene regulation, but how they control the expression and activity of ion channel genes in the heart remains unclear. Here, we show that Nup50, which is localized in the nucleus of cardiomyocytes, selectively induces an increase in the transcription and translation of Kcna4. The Kcna4 gene encodes a K+ voltage-gated channel of shaker-related subfamily member 4 and is essential for regulating the action potential in cardiac membranes. Using immunofluorescence imaging, luciferase assays and chromatin immunoprecipitation assays, we identified that the direct binding of the FG-repeat domain within Nup50 to the proximity of the Kcna4 promoter was required to activate the transcription and subsequent translation of Kcna4. Functionally, Nup50 overexpression increased the currents of KCNA4-encoded Ito,s channels, and reverse knockdown of Nup50 resulted in a remarkable decrease in the amplitude of Ito,s currents in cardiomyocytes. Moreover, a positive correlation between Nup50 and Kcna4 mRNA and protein expression was observed in heart tissues subjected to ischemic insults. These findings provide insights into the homeostatic control of cardiac electrophysiology through Nup-mediated regulation.

中文翻译：

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核孔蛋白 50 介导 Kcna4 转录以调节心脏电活动。

新出现的证据表明，核孔蛋白 (Nups) 在细胞类型特异性基因调控中起关键作用，但它们如何控制心脏中离子通道基因的表达和活性仍不清楚。在这里，我们展示了位于心肌细胞核中的 Nup50，选择性地诱导了 Kcna4 转录和翻译的增加。Kcna4 基因编码振动器相关亚家族成员 4 的 K+ 电压门控通道，对于调节心脏膜中的动作电位至关重要。使用免疫荧光成像、荧光素酶测定和染色质免疫沉淀测定，我们发现 Nup50 内的 FG 重复结构域与 Kcna4 启动子附近的直接结合是激活 Kcna4 的转录和后续翻译所必需的。在功能上，Nup50 过表达增加了 KCNA4 编码的 Ito,s 通道的电流，并且 Nup50 的反向敲低导致心肌细胞中 Ito,s 电流的幅度显着降低。此外，在遭受缺血性损伤的心脏组织中观察到 Nup50 和 Kcna4 mRNA 和蛋白质表达之间的正相关。这些发现为通过 Nup 介导的调节对心脏电生理学的稳态控制提供了见解。