Serum and glucocorticoid inducible kinase regulates hERG channels through inhibition of Nedd4–2 and activation of Rab11 recycling endosomes

Abstract

The human ether‐a‐go‐go‐related gene (hERG) encodes the rapidly activating delayed rectifier potassium channel (IKr). Loss of function of hERG channels due to mutations or drug‐induced blockage can cause long QT syndrome, leading to ventricular arrhythmias or sudden death. Physical or emotional stress is known to affect ion channel activity. Stress hormones such as cortisol regulate the expression of various genes including the serum‐ and glucocorticoid‐inducible kinase (SGK). Using patch clamp, Western blot, co‐immunoprecipitation, and immunocytochemistry methods, we demonstrate that SGK isoforms SGK1 and SGK3 increased hERG current (IHERG) and the expression level of mature hERG proteins. We recently showed that mature hERG channels are degraded by ubiquitin ligase Nedd4–2 via enhanced ubiquitination. We observed that SGK1 and SGK3 overexpression enhanced Nedd4–2 phosphorylation which is known to inhibit Nedd4–2 activity. However, removal of the Nedd4–2 effect on hERG channels by disrupting Nedd4–2 target motif in hERG reduced but did not eliminate the SGK‐induced increase in hERG expression. Additional disruption of Rab11 proteins led to a complete elimination of SGK‐mediated hERG increase. We conclude that SGK isoforms 1 and 3 enhance hERG stability by inhibiting Nedd4–2 ubiquitin ligase and activating Rab11 recycling endosomes.Supported by: Canadian Institutes of Health Research (CIHR)