SGK3 Sensitivity of Voltage Gated K ⁺ Channel K _v1.5 (KCNA5)

Background: The serum & glucocorticoid inducible kinase isoform SGK3 is a powerful regulator of several transporters, ion channels and the Na ⁺ /K ⁺ ATPase. Targets of SGK3 include the ubiquitin ligase Nedd4-2, which is in turn a known regulator of the voltage gated K ⁺ channel K _v1.5 (KCNA5). The present study thus explored whether SGK3 modifies the activity of the voltage gated K ⁺ channel KCNA5, which participates in the regulation of diverse functions including atrial cardiac action potential, activity of vascular smooth muscle cells, insulin release and tumour cell proliferation. Methods: cRNA encoding KCNA5 was injected into Xenopus oocytes with and without additional injection of cRNA encoding wild-type SGK3, constitutively active ^S419D SGK3, inactive ^K191N SGK3 and/or wild type Nedd4-2. Voltage gated K ⁺ channel activity was quantified utilizing dual electrode voltage clamp. Results: Voltage gated current in KCNA5 expressing Xenopus oocytes was significantly enhanced by wild-type SGK3 and ^S419D SGK3, but not by ^K191N SGK3. SGK3 was effective in the presence of ouabain (1 mM) and thus did not require Na ⁺ /K ⁺ ATPase activity. Coexpression of Nedd4-2 decreased the voltage gated current in KCNA5 expressing Xenopus oocytes, an effect largely reversed by additional coexpression of SGK3. Conclusion: SGK3 is a positive regulator of KCNA5, which is at least partially effective by abrogating the effect of Nedd4-2.