SNX17（分选连接蛋白 17）通过内吞转运 Kv1.5（电压门控钾通道亚家族 A 成员 5）通道介导心房颤动的发生。
SNX17 (Sorting Nexin 17) Mediates Atrial Fibrillation Onset Through Endocytic Trafficking of the Kv1.5 (Potassium Voltage-Gated Channel Subfamily A Member 5) Channel.
机构信息
Key Laboratory of Arrhythmias of the Ministry of Education of East Hospital (L.G., S.W., F.Z., K.X., J.H., T.Z., D.S., F.L., D.L., Y.C., Y.L., D.X., Y.-H.C.), Tongji University, Shanghai, China.
Institute of Medical Genetics (L.G., S.W., F.Z., K.X., J.H., T.Z., D.S., F.L., L.L., D.L., Y.C., Y.L., D.X., Y.-H.C.), Tongji University, Shanghai, China.
出版信息
Circ Arrhythm Electrophysiol. 2019 Apr;12(4):e007097. doi: 10.1161/CIRCEP.118.007097.
BACKGROUND
Kv1.5 (Potassium voltage-gated channel subfamily A member 5) has been regarded as a promising target of interventions for atrial fibrillation (AF). SNX17 (sorting nexin 17), a member of the SNXs (sorting nexin family), regulates the intracellular trafficking of membrane proteins through its FERM (four-point-one, ezrin, radixin, moesin) domain. However, whether SNX17 regulates the trafficking process of Kv1.5 remains unknown.
METHODS
A SNX17 knockout rat line was generated to test the role of SNX17 in atrial electrophysiology. The protein expression of SNX17 and membrane ion channels was detected by Western blotting. Electrophysiology changes in the atrial tissue and myocytes were analyzed by optical mapping and patch clamp, respectively. Acetylcholine and electrical stimulation were used to induce AF, and ECG recording was adopted to assess the influence of SNX17 deficiency on AF susceptibility. The spatial relationship between Kv1.5 and SNX17 was evaluated by immunostaining and confocal scanning, and the functional region of SNX17 regulating Kv1.5 trafficking was identified using plasmids with truncated SNX17 domains.
RESULTS
Embryonic death occurred in homozygous SNX17 knockout rats. SNX17 heterozygous rats survived, and the level of the SNX17 protein in the atrium was decreased by ≈50%. SNX17 deficiency increased the membrane expression of Kv1.5 and atria-specific ultrarapid delayed rectifier outward potassium current ( I) density, resulting in a shortened action potential duration, and eventually contributing to AF susceptibility. Mechanistically, SNX17 facilitated the endocytic sorting of Kv1.5 from the plasma membrane to early endosomes via the FERM domain.
CONCLUSIONS
SNX17 mediates susceptibility to AF by regulating endocytic sorting of the Kv1.5 channel through the FERM domain. SNX17 could be a potential target for the development of new drugs for AF.
背景
Kv1.5（钾电压门控通道亚家族 A 成员 5）已被视为干预心房颤动（AF）的有希望的靶点。SNX17（分选连接蛋白 17）是 SNXs（分选连接蛋白家族）的成员之一，通过其 FERM（四一体、埃兹林、根蛋白、膜突蛋白）结构域调节膜蛋白的细胞内转运。然而，SNX17 是否调节 Kv1.5 的转运过程尚不清楚。
方法
生成 SNX17 敲除大鼠品系，以测试 SNX17 在心房电生理中的作用。通过 Western blot 检测 SNX17 和膜离子通道的蛋白表达。通过光学映射和膜片钳分别分析心房组织和心肌细胞的电生理变化。采用乙酰胆碱和电刺激诱导 AF，采用心电图记录评估 SNX17 缺乏对 AF 易感性的影响。通过免疫染色和共焦扫描评估 Kv1.5 和 SNX17 之间的空间关系，并使用截断 SNX17 结构域的质粒鉴定调节 Kv1.5 转运的 SNX17 功能区。
结果
纯合 SNX17 敲除大鼠胚胎死亡。SNX17 杂合子大鼠存活，心房中 SNX17 蛋白水平降低约 50%。SNX17 缺乏增加了 Kv1.5 的膜表达和心房特异性超快延迟整流外向钾电流（I）密度，导致动作电位时程缩短，最终导致 AF 易感性增加。机制上，SNX17 通过 FERM 结构域促进 Kv1.5 从质膜到早期内体的内吞分拣。
结论
SNX17 通过 FERM 结构域调节 Kv1.5 通道的内吞分拣来介导 AF 的易感性。SNX17 可能成为 AF 新药开发的潜在靶点。
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