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Background  The AGC protein kinase family regulates multiple cellular functions. 3-phosphoinositide-dependent protein kinase-1 ( PDK1 ) is involved in the pathogenesis of arrhythmia, and its downstream factor, Forkhead box O1 (Foxo1), negatively regulates the expression of the cardiac sodium channel, Nav1.5. Mice are known to die suddenly after  PDK1  deletion within 11 weeks, but the underlying electrophysiological bases are unclear. Thus, the aim of this study was to investigate the potential mechanisms between  PDK1  signaling pathway and cardiac sodium current.    Methods and Results  Using patch clamp and western blotting techniques, we investigated the role of the  PDK1 -Foxo1 pathway in  PDK1  knockout mice and cultured cardiomyocytes. We found that  PDK1  knockout mice undergo slower heart rate, prolonged QRS and QTc intervals and abnormal conduction within the first few weeks of birth. Furthermore, the peak sodium current is decreased by 33% in cells lacking  PDK1 . The phosphorylation of Akt (308T) and Foxo1 (24T) and the expression of Nav1.5 in the myocardium of  PDK1 -knockout mice are decreased, while the nuclear localization of Foxo1 is increased. The role of the  PDK1 -Foxo1 pathway in regulating Nav1.5 levels and sodium current density was verified using selective  PDK1 , Akt and Foxo1 inhibitors and isolated neonatal rat cardiomyocytes.    Conclusion  These results indicate that  PDK1  participates in the dysregulation of electrophysiological basis by regulating the  PDK1 -Foxo1 pathway, which in turn regulates the expression of Nav1.5 and cardiac sodium channel function.

Deletion of PDK1 Causes Cardiac Sodium Current Reduction in Mice