Abstract
Alterations in sodium flux (INa) play an important role in the pathogenesis of cardiac arrhythmias and may also contribute to the development of cardiomyopathies. We have recently demonstrated a critical role for the regulation of the voltage-gated sodium channel NaV1.5 in the heart by the serum and glucocorticoid regulated kinase-1 (SGK1). Activation of SGK1 in the heart causes a marked increase in both the peak and late sodium currents leading to prolongation of the action potential duration and an increased propensity to arrhythmia. Here we show that SGK1 directly regulates NaV1.5 channel function, and genetic inhibition of SGK1 in a zebrafish model of inherited long QT syndrome rescues the long QT phenotype. Using computer-aided drug discovery coupled with in vitro kinase assays, we identified a novel class of SGK1 inhibitors. Our lead SGK1 inhibitor (5377051) selectively inhibits SGK1 in cultured cardiomyocytes, and inhibits phosphorylation of an SGK1-specific target as well as proliferation in the prostate cancer cell line, LNCaP. Finally, 5377051 can reverse SGK1’s effects on NaV1.5 and shorten the action potential duration in induced pluripotent stem cell (iPSC)-derived cardiomyocytes from a patient with a gain-of-function mutation in Nav 1.5 (Long QT3 syndrome). Our data suggests that SGK1 inhibitors warrant further investigation in the treatment of cardiac arrhythmias.
Highlights
Sudden cardiac death (SCD) is a leading contributor to mortality in the United States
Computer Aided Drug Discovery (CADD) approach successfully identified a novel class of serum and glucocorticoid-regulated kinase-1 (SGK1) inhibitory compounds
In the absence of a high resolution structure of active SGK1 determined by X-ray crystallography or NMR spectroscopy at the time of the screening, we used comparative protein modeling to build a three-dimensional model for SGK1 based on known crystal structures of related proteins with acceptable sequence homology and protein folds
Summary
Sudden cardiac death (SCD) is a leading contributor to mortality in the United States. Chronic SGK1 activation in cardiomyocytes leads to a marked alteration in the sodium flux (but not of K+ or Ca2+ fluxes), prolongation of action potential duration (APD) in cardiomyocytes (CMs) and a markedly increased propensity for lethal ventricular arrhythmias[4]. These studies raise the possibility that small molecule inhibitors would be anti-arrhythmic in cardiac diseases through correction of abnormal INa while having little or no adverse consequences in normal hearts. SGK1 is in the rare category of kinases, whose inhibition may be of benefit both in heart disease and cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
