Airway function is dependent upon the absorption of Na+ from the airway surface liquid and this ENaC-dependent process is regulated by glucocorticoids. These hormones induce expression SGK1 (see e.g. Cohen & Lang, 2001), a regulatory kinase that seems to stimulate Na+ transport by increasing the surface abundance of ENaC subunits. The catalytic activity of SGK1 is dependent upon the phosphoinositide-3-kinase (PI3K)-controlled phosphorylation of SGK1-Ser422 by the mammalian target of rapamycin signalling complex 2 (TORC2) (García-Martínez & Alessi, 2008) and, to clarify the mechanism that allows gluccorticoids to control ENaC, we now explore the effects of inhibitors of TORC2 (TORIN1) and SGK1 (GSK650394) upon the glucocorticoid-induced epithelial Na+ current (Clunes et al., 2004) and SGK1 activity (assayed by monitoring the phosphorylation of NDRG1-Thr346/356/366, an endogenous SGK1 substrate, see Inglis et al. 1999) in H441 cells. Initial studies confirmed (see Clunes et al., 2004) that ~24 h exposure to 0.2 µM dexamethasone depolarizes Vm (Fig 1A) by inducing amiloride-sensitive Na+current(Fig. 1B). This glucocorticoid-induced current was abolished by TORIN1 (Fig. 1C) or GSK650394 (Fig 1D). Although TORIN1 inhibits TORC1 as well as TORC2, this cannot explain the present effect since rapamycin, a selective TORC1 inhibitor, had no effect (Fig. 1E). Analyses of extracted proteins (n = 4) showed that TORIN1 (0.1 µM, 3 h) and GSK650394 (10 µM, 3 h), but not rapamycin (0.1 µM, 3 h), also blocked NDRG1-Thr346/356/366 phosphorylation indicating inactivation of this kinase. These compounds did not, however, suppress the PI3K-dependent phosphorylation of protein kinase B-Thr308 demonstrating that PI3K activity is retained. Glucocorticoid-induced ENaC activity in H441 cells is therefore dependent upon TORC2 / SGK1 but, despite this finding, subsequent studies showed that dexamethasone (0.2 µM, ~24 h, n = 5) did not stimulate NDRG1-Thr346/356/366 phosphorylation. Moreover, whilst increased phosphorylation of this SGK1 substrate was evident in cells exposed to dexamethasone 3 h, brief (3 – 4 h) exposure to dexamethasone did not alter the electrical properties of H441 cells (n = 5). The glucocorticoid-induced Na+ currents in these cells thus develop relatively slowly but are maintained whilst SGK1 activation is more rapid and transient. It is therefore clear that hormone-induced ENaC activation does not coincide with the increased activity of SGK1 and so, whilst SGK1 is clearly important, our data suggest that the role of this kinase is permissive.