Activation of SGK1 and SGK3 increases hERG expression by inhibiting Nedd4-2 activity and promoting Rab11-mediated hERG recycling.
SGK1 and SGK3 regulate hERG channel expression through Nedd4-2 inhibition and Rab11-mediated recycling, extending understanding of cardiac electrophysiology.
The hERG (human ether-a-go-go-related gene) encodes the α subunit of the rapidly activating delayed rectifier potassium channel (I Kr ). Dysfunction of hERG channels due to mutations or certain medications causes long QT syndrome, which can lead to fatal ventricular arrhythmias or sudden death. Although the abundance of hERG in the plasma membrane is a key determinant of hERG functionality, the mechanisms underlying its regulation are not well understood. In the present study, we demonstrated that overexpression of the stress-responsive serum- and glucocorticoid-inducible kinase (SGK) isoforms SGK1 and SGK3 increased the current and expression level of the membrane-localized mature proteins of hERG channels stably expressed in HEK 293 (hERG-HEK) cells. Furthermore, the synthetic glucocorticoid, dexamethasone, increased the current and abundance of mature ERG proteins in both hERG-HEK cells and neonatal cardiac myocytes through the enhancement of SGK1 but not SGK3 expression. We have previously shown that mature hERG channels are degraded by ubiquitin ligase Nedd4-2 via enhanced channel ubiquitination. Here, we showed that SGK1 or SGK3 overexpression increased Nedd4-2 phosphorylation, which is known to inhibit Nedd4-2 activity. Nonetheless, disruption of the Nedd4-2 binding site in hERG channels did not eliminate the SGK-induced increase in hERG expression. Additional disruption of Rab11 proteins led to a complete elimination of SGK-mediated increase in hERG expression. These results show that SGK enhances the expression level of mature hERG channels by inhibiting Nedd4-2 as well as by promoting Rab11-mediated hERG recycling. Background: The cardiac hERG (I Kr ) potassium channel is important for cardiac repolarization. Results: Activation of SGK1 and SGK3 increases hERG expression by inhibiting Nedd4-2 activity and promoting Rab11-mediated hERG recycling. Conclusion: SGK1 and SGK3 regulate hERG through Nedd4-2 and Rab11 pathways. Significance: Identification of SGK effects on hERG extends our understanding of ion channel regulation and cardiac electrophysiology.
Lamothe et al. (2013) studied this question. SGK1 and SGK3 overexpression / dexamethasone was evaluated on hERG channel current and expression level. Activation of SGK1 and SGK3 increases hERG expression by inhibiting Nedd4-2 activity and promoting Rab11-mediated hERG recycling.