α‐ENaC expression and activity is regulated by a variety of hormones including β‐adrenergic agonists via the second messenger cAMP. We evaluated the early intermediate pathways involved in the up‐regulation of SGK1 by DbcAMP and whether SGK1 is a prerequisite for induction of α‐ENaC expression. Submandibular gland epithelial (SMG‐C6) cells treated with DbcAMP (1 mM) induced both SGK1 mRNA and protein expression. DbcAMP‐stimulated SGK1 mRNA expression was decreased by actinomycin D and mRNA and protein expressions were attenuated by PKA inhibitors (H‐89 and KT5720). Inhibition of PI3‐K with either LY294002 or dominant negative PI3‐K reduced DbcAMP‐stimulated SGK1 protein and mRNA levels, attenuated the phosphorylation of CREB (a cAMP‐activated transcription factor) and decreased α‐ENaC protein levels and Na⁺ transport. In addition, the combination of PKA inhibitors with dominant negative PI3‐K synergistically inhibited DbcAMP‐induced Na⁺ transport. Inhibition of SGK1 expression by siRNA decreased but did not obliterate DbcAMP‐induced α‐ENaC expression. Thus, in a cell line which endogenously exhibits minimal α‐ENaC expression, induction of SGK1 by DbcAMP occurs via the PI3‐K and PKA pathways. Increased α‐ENaC levels and function are partly dependent upon the early induction of SGK1 expression. J. Cell. Physiol. 217: 632–642, 2008. © 2008 Wiley‐Liss, Inc.