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Stress-Kinase Regulation of TASK-1 and TASK-3

机译：TASK-1和TASK-3的应激激酶调节

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>Background/Aims: TASK channels belong to the two-pore-domain potassium (K2P) channel family. TASK-1 is discussed to contribute to chronic atrial fibrillation (AFib) and has been together with uncoupling protein 1 found as a marker protein of brown adipose tissue (BAT) fat. In addition, TASK-1 was linked in a genome-wide association study to an increased body mass index. A recent study showed that TASK-1 inhibition is causing obesity in mice by a BAT whitening and that these effects are linked to the mineralocorticoid receptor pathway, albeit the mechanism remained elusive. Therefore, we aimed to probe whether K2P channels are regulated by serum- and glucocorticoid-inducible kinases (SGKs) which are known to modify many cellular functions by modulating ion channels. Methods: To this end we used functional co-expression studies and chemiluminescence-assays in Xenopus oocytes, together with fluorescence imaging and quantitative PCR experiments. Results: SGKs and proteinkinase B (PKB) induced a strong, dose- and time-dependent current reduction of TASK-1 and TASK-3. SGK co-expression reduced the surface expression of TASK-1/3, leading to a predominant localization of the channels into late endosomes. The down regulation of TASK-3 channels was abrogated by the dynamin inhibitor dynasore, confirming a role of SGKs in TASK-1/3 channel endocytosis. Conclusion: Stress-mediated changes in SGK expression pattern or activation is likely to alter TASK-1/3 expression at the surface membrane. The observed TASK-1 regulation might contribute to the pathogenesis of chronic AFib and provide a mechanistic link between increased mineralocorticoid levels and TASK-1 reduction, both linked to BAT whitening.
机译：> 背景/目标： TASK通道属于两孔域钾（K 2P ）通道家族。讨论了TASK-1有助于慢性心房纤颤（AFib），并将其与作为棕色脂肪组织（BAT）脂肪标记蛋白的解偶联蛋白1一起使用。另外，TASK-1在全基因组关联研究中与增加的体重指数相关。最近的一项研究表明，通过BAT增白，TASK-1的抑制作用正在引起小鼠肥胖，这些作用与盐皮质激素受体途径有关，尽管其机理尚不清楚。因此，我们旨在探讨K 2P 通道是否受血清和糖皮质激素诱导的激酶（SGKs）调节，这些激酶已知可通过调节离子通道来修饰许多细胞功能。 方法： 为此，我们在非洲爪蟾（ienopus）卵母细胞中使用了功能共表达研究和化学发光分析，以及荧光成像和定量PCR实验。 结果： SGK和蛋白激酶B（PKB）诱导了TASK-1和TASK-3的强烈，剂量和时间依赖性的电流减少。 SGK共表达降低了TASK-1 / 3的表面表达，导致通道主要定位于晚期内体。动态抑制剂抑制剂的作用消除了TASK-3通道的下调，从而证实了SGK在TASK-1 / 3通道内吞中的作用。 结论： 应激介导的SGK表达模式或激活的改变可能会改变表面膜上的TASK-1 / 3表达。观察到的TASK-1调节可能有助于慢性AFib的发病机理，并在盐皮质激素水平升高和TASK-1减少之间建立了机械联系，两者均与BAT增白有关。

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