HERG trafficking and pharmacological rescue of LQTS-2 mutant channels

The human ether-a-go-go-related gene (hERG) encodes an ion channel subunit underlying IKr, a potassium current required for the normal repolarization of ventricular cells in the human heart. Mutations in hERG cause long QT syndrome (LQTS) by disrupting IKr, increasing cardiac excitability and, in some cases, triggering catastrophic torsades de pointes arrhythmias and sudden death. More than 200 putative disease-causing mutations in hERG have been identified in affected families to date, but the mechanisms by which these mutations cause disease are not well understood. Of the mutations studied, most disrupt protein maturation and reduce the numbers of hERG channels at the membrane. Some trafficking-defective mutants can be rescued by pharmacological agents or temperature. Here we review evidence for rescue of mutant hERG subunits expressed in heterologous systems and discuss the potential for therapeutic approaches to correcting IKr defects associated with LQTS.