Human ether-a-go-go-related gene (hERG) channels conduct delayed rectifier K(+) 
current. However, little information is available on physiological situations 
affecting hERG channel protein and function. In the present study we examined 
the effects of intermittent hypoxia (IH), which is a hallmark manifestation of 
sleep apnea, on hERG channel protein and function. Experiments were performed on 
SH-SY5Y neuroblastoma cells, which express hERG protein. Cells were exposed to 
IH consisting of alternating cycles of 30 s of hypoxia (1.5% O2) and 5 min of 
20% O2. IH decreased hERG protein expression in a stimulus-dependent manner. A 
similar reduction in hERG protein was also seen in adrenal medullary chromaffin 
cells from IH-exposed neonatal rats. The decreased hERG protein was associated 
with attenuated hERG K(+) current. IH-evoked hERG protein degradation was not 
due to reduced transcription or increased proteosome/lysomal degradation. Rather 
it was mediated by calcium-activated calpain proteases. Both COOH- and 
NH2-terminal sequences of the hERG protein were the targets of calpain-dependent 
degradation. IH increased reactive oxygen species (ROS) levels, intracellular 
Ca(2+) concentration ([Ca(2+)]i), calpain enzyme activity, and hERG protein 
degradation, and all these effects were prevented by 
manganese-(111)-tetrakis-(1-methyl-4-pyridyl)-porphyrin pentachloride, a 
membrane-permeable ROS scavenger. These results demonstrate that activation of 
calpains by ROS-dependent elevation of [Ca(2+)]i mediates hERG protein 
degradation by IH.