To study a cAMP-mediated signaling pathway in the regulation of amiloride-sensitive Na(+) transport in rat fetal distal lung epithelial cells, we measured an amiloride-sensitive short-circuit current (Na(+) transport). Forskolin, which increases the cytosolic cAMP concentration, stimulated the Na(+) transport. Forskolin also activated cAMP-dependent protein kinase (PKA). A beta-adrenergic agonist and cAMP mimicked the forskolin action. PKA inhibitors KT-5720, H-8, and myristoylated PKA-inhibitory peptide amide-(14-22) did not influence the forskolin action. These results suggest that forskolin stimulates Na(+) transport through a PKA-independent pathway. Furthermore, forskolin increased tyrosine phosphorylation of approximately 70- to 80-, approximately 97-, and approximately 110- to 120-kDa proteins. Protein tyrosine kinase (PTK) inhibitors (tyrphostin A23 and genistein) abolished the forskolin action. Moreover, 5-nitro-2-(3-phenylpropylamino)benzoate (a Cl(-)-channel blocker) prevented the stimulatory action of forskolin on Na(+) transport via abolishment of the forskolin-induced cell shrinkage and tyrosine phosphorylation. Based on these results, we conclude that forskolin (and cAMP) stimulates Na(+) transport in a PTK-dependent but not a PKA-dependent pathway by causing cell shrinkage, which activates PTK in rat fetal distal lung epithelial cells.
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Niisato et al. (1999) studied this question.