Calpain activation by ROS mediates human ether-a-go-go-related gene protein degradation by intermittent hypoxia

Area of Science:

• Cardiovascular Physiology
• Molecular Biology
• Sleep Medicine

Background:

• Human ether-a-go-go-related gene (hERG) channels are crucial for cardiac electrical activity.
• The impact of physiological stressors like intermittent hypoxia (IH) on hERG protein expression and function remains largely unexplored.

Purpose of the Study:

• To investigate the effects of IH, a key feature of sleep apnea, on hERG channel protein and function.
• To elucidate the molecular mechanisms underlying IH-induced changes in hERG.

Main Methods:

• SH-SY5Y neuroblastoma cells and neonatal rat adrenal medullary chromaffin cells were exposed to IH.
• hERG protein expression, K+ current, reactive oxygen species (ROS) levels, intracellular calcium ([Ca2+]i), and calpain activity were measured.
• The role of calpains and ROS was assessed using specific inhibitors and scavengers.

Main Results:

• IH significantly decreased hERG protein expression and attenuated hERG K+ current in a stimulus-dependent manner.
• IH-induced hERG degradation was mediated by calcium-activated calpain proteases, not by reduced transcription or increased proteasomal/lysosomal degradation.
• IH elevated ROS levels, [Ca2+]i, and calpain activity, all of which were mitigated by a ROS scavenger.

Conclusions:

• IH leads to hERG protein degradation through calpain activation, triggered by ROS-dependent increases in intracellular calcium.
• These findings reveal a novel molecular pathway linking sleep apnea-related hypoxia to potential cardiac channel dysfunction.