Serum- and glucocorticoid-inducible kinases (SGK) regulate KCNQ1/KCNE potassium channels.

The stress reaction includes the release of stress hormones such as cortisol via the HPA axis4. One of the genes regulated by cortisol is the serum- and glucocorticoid-inducible kinase 1 (SGK1) a stimulator of the slow outward potassium channel KCNQ1/KCNE1-one of the major mediators of cardiac repolarization. Apart from KCNE1, several other KCNE beta subunits including KCNE3 and KCNE5 have been detected at the mRNA level in cardiac tissue as well as in the inner ear and the gastro-intestinal tract. Here, we extend our previous investigations to KCNQ1/KCNE3 channels and their modulation by SGKs. We show that these channels are not stimulated by any of the three SGK isoforms when expressed in a heterologous expression system. 3D docking simulations suggest that crucial residues within KCNQ1 and KCNE1 are co-localized to a region close to the putative inner phase of the membrane, suggesting a key region important for channel complex sorting into vesicles. Identification of the KCNQ1/KCNE recycling pathway and its modulation by SGK provides a mechanistic insight into stress-induced modulation of KCNQ1/KCNE channels.