Contrasting Effects of Sustained and Intermittent Hypoxia on HERG K+ Channel Trafficking

Human ether‐go‐go‐related gene (hERG) K + channel mediates a variety of cellular functions including cell excitability. In the present study, we examined the effects of intermittent hypoxia (IH) and sustained hypoxia (SH) on hERG currents and trafficking in neuroblastoma cells (SH‐SY5Y). Patch‐clamp studies revealed that both IH and SH decreased hERG tail currents by 40–50%. IH decreased the expression of surface and the endoplasmic reticulum (ER) hERG forms in a stimulus‐dependent and irreversible manner. In contrast, SH down‐ regulated surface expression of hERG protein with accumulation of the ER form in a stimulus dependent but reversible manner. IH‐evoked downregulation of hERG was not due to increased proteosome/lysosomal degradation; whereas SH‐evoked degradation was blocked by lysosomal inhibitor baflomycin. Calcium chelator (BAPTA) and inhibitors of calpain proteases (ALLM, PD90185) prevented IH‐ but not SH‐ evoked hERG degradation suggesting a role for Ca 2+ dependent calpains. Basal [Ca 2+ ] I and calpain activities were elevated in IH but not in SH treated cells. These studies demonstrate that IH and SH regulate hERG expression and function by different mechanisms. Supported by HL‐90554, HL‐76537, HL‐86493 and HL‐089616.