Aquaporin-5 (AQP5) is selectively expressed in the apical membrane of exocrine glands, such as salivary and lacrimal, and plays important roles to maintain their secretory functions. Because AQP5 is not regulated by structural gating, translocation between plasma membrane and intracellular space is important for its water-permeable function. We and other groups have been shown that intracellular Ca²⁺-dependent signaling increases AQP5 translocation to plasma membrane. On the other hand, the role of cAMP/PKA-dependent signaling on AQP5 translocation is still unclear, although phosphorylation of AQP5 by PKA has been suggested. In several secretory cells, interaction between cAMP and Ca²⁺ signals regulate their function. In this study, therefore, we examined the combined effect of Ca²⁺ ionophore and PKA activator on subcellular localization of AQP5. In MLE-12 cells, ionomycin alone increased AQP5 translocation to plasma membrane, whereas forskolin alone did not. The combined effect of ionomycin and forskolin was considerably greater than that of ionomycin alone. This enhancement of the effect of ionomycin by forskolin was inhibited by H-89, a PKA inhibitor. Now we are investigating whether PKA-dependent phosphorylation of AQP5 is involved in this potentiated translocation.