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1 Department of Physiology, Emory University, Atlanta, GA, USA; Center for Cell and Molecular Signaling, Emory University, Atlanta, GA, USA
2 Department of Pediatrics, Emory University, Atlanta, GA, USA; Center for Cell and Molecular Signaling, Emory University, Atlanta, GA, USA
3 Department of Pediatrics, Emory University, Atlanta, GA, USA; Department of Physiology, Emory University, Atlanta, GA, USA; Center for Cell and Molecular Signaling, Emory University, Atlanta, GA, USA
* To whom correspondence should be addressed. E-mail: deaton{at}emory.edu.
Dopamine can increase lung fluid clearance. This is, at least in part, due to activation of the basolateral Na,K-ATPase. However, activation of Na,K-ATPase by itself is unlikely to produce large changes in transepithelial transport. Therefore, in this work, we examined the effect of apical and basolateral dopamine on apical, highly-selective sodium channels (ENaC) in monolayers of an alveolar type 2 (AT2) model cell line (L2). Dopamine increased channel open probability (Po) without changing the unitary current. The D1 receptor blocker, SCH23390 (10 µM), blocked the dopamine effect, but the D2 receptor blocker, sulpride, did not. The dopamine-mediated increase in ENaC activity was not a secondary effect of dopamine stimulation of Na,K-ATPase, since 1 mM ouabain applied to the basolateral side of L2 cells to block the activity of Na,K-ATPase did not alter the effect of apical dopamine on ENaC activity. Protein Kinase A (PKA) was not responsible for the dopamine effect since a PKA inhibitor, H89, did not reduce the effect of dopamine. On the other hand, cpt-2-O-Me-cAMP, which selectively binds and activates EPAC (exchange protein activated by cAMP) but not PKA, increased ENaC open probability. A Src inhibitor, PP2, and the phosphotidylinositol-3-kinase inhibitor, LY294002, blocked the effect of dopamine on ENaC. In addition, a MEK blocker, U0126, an inhibitor of phospholipase A2, and a protein phosphatase inhibitor also blocked the effect of dopamine on ENaC activity. Finally, since the cAMP-EPAC-Rap1 pathway also activates DARPP 32 (dopamine response protein phosphatase), we confirmed that dopamine phosphorylates DARPP 32, and addition of okadaic acid, which blocks phosphatases (DARPP 32), also blocks dopamine effect. In summary, dopamine increases ENaC activity by a cAMP-mediated alternative signaling pathway that involves EPAC and Rap1, signaling molecules usually associated with growth factor-activated receptors.
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