Intracellular Ca2+ modulates hERG channel expression involving Ca2+/calmodulin-dependent kinase and MEK-ERK pathways

The hERG channel (Kv11.1 potassium channel) is the main carrier of the cardiac rapid delayed rectifier potassium current (Iₖᵣ), which plays a crucial role in the repolarization of the cardiac action potential. This study investigates the effect of intracellular Ca2+ signaling on the expression and function of the hERG channel. The results show that Ca2+ significantly upregulates hERG mRNA expression and IhERG or Iₖᵣ current density with pharmacological evidence implicating Ca2+/calmodulin-dependent kinase (CaMK) and mitogen-activated protein kinase kinase-extracellular signal-regulated kinase (MEK-ERK) signaling, while the effects of calcineurin and nuclear factor of activated T-cells (NFAT) signaling on this process are negligible. Based on the results of inhibitor experiments, the regulation is dependent on gene transcription and protein translation processes. This study provides pharmacological evidence suggesting that CaMK- and MEK-ERK-related pathways may be involved in Ca2+-mediated modulation of hERG channel activity, providing new insights into arrhythmia-related ion channel regulation.