We investigated targeting mechanisms of Na⁺ and K_ATP channels to the intercalated disk (ICD) of cardiomyocytes. Patch clamp and surface biotinylation data show reciprocal downregulation of each other's surface density. Mutagenesis of the Kir6.2 ankyrin binding site disrupts this functional coupling. Duplex patch clamping and Angle SICM recordings show that I_Na and I_KATP functionally co-localize at the rat ICD, but not at the lateral membrane. Quantitative STORM imaging show that Na⁺ and K_ATP channels are localized close to each other and to AnkG, but not to AnkB, at the ICD. Peptides corresponding to Nav1.5 and Kir6.2 ankyrin binding sites dysregulate targeting of both Na⁺ and K_ATP channels to the ICD, but not to lateral membranes. Finally, a clinically relevant gene variant that disrupts K_ATP channel trafficking also regulates Na⁺ channel surface expression. The functional coupling between these two channels need to be considered when assessing clinical variants and therapeutics.

中文翻译：

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锚蛋白-G介导Na +和KATP通道靶向大鼠心脏插层盘

我们调查了Na ⁺和K _ATP通道靶向心肌细胞插入盘（ICD）的靶向机制。膜片钳和表面生物素化数据显示彼此表面密度的相互下调。Kir6.2锚蛋白结合位点的诱变破坏了这种功能性耦合。双面膜片钳夹和Angle SICM记录显示I _Na和I _KATP在功能上共定位于大鼠ICD，但不在侧膜。定量STORM成像显示，ICD处Na ⁺和K _ATP通道彼此靠近且靠近AnkG，而不是AnkB。对应于Nav1.5和Kir6.2锚蛋白结合位点的肽对两个Na的靶向失调⁺和K _ATP通道通向ICD，但不通向侧膜。最后，破坏K _ATP通道运输的临床相关基因变体也调节Na ⁺通道表面表达。在评估临床变异和治疗方法时，需要考虑这两个通道之间的功能耦合。