Dopamine regulation of amiloride-sensitive sodium channels in lung cells

被引:61
作者
Helms, MN
Chen, XJ
Ramosevac, S
Eaton, DC
Jain, L
机构
[1] Emory Univ, Sch Med, Dept Physiol, Atlanta, GA 30322 USA
[2] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA 30322 USA
[3] Emory Univ, Sch Med, Ctr Cell & Mol Signaling, Atlanta, GA 30322 USA
关键词
single channel recording; ion transport; epithelial sodium channels; L2 lung cells; exchange protein activated by cAMP;
D O I
10.1152/ajplung.00486.2004
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
Dopamine increases lung fluid clearance. This is partly due to activation of basolateral Na-K-ATPase. However, activation of Na-K-ATPase by itself is unlikely to produce large changes in transepithelial transport. Therefore, we examined apical and basolateral dopamine's effect on apical, highly selective sodium channels [epithelial sodium channels (ENaC)] in monolayers of an alveolar type 2 cell line (L2). Dopamine increased channel open probability (P-o) without changing the unitary current. The D1 receptor blocker SCH-23390 blocked the dopamine effect, but the D2 receptor blocker sulpiride did not. The dopamine-mediated increase in ENaC activity was not a secondary effect of dopamine stimulation of Na-K-ATPase, since ouabain applied to the basolateral surface to block the activity of Na-K-ATPase did not alter dopamine-mediated ENaC activity. Protein kinase A (PKA) was not responsible for dopamine's effect since a PKA inhibitor, H89, did not reduce dopamine's effect. However, cpt-2-O-Me-cAMP, which selectively binds and activates EPAC (exchange protein activated by cAMP) but not PKA, increased ENaC P-o. An Src inhibitor, PP2, and the phosphatidylinositol-3-kinase inhibitor, LY-294002, blocked dopamine's effect on ENaC. In addition, an MEK blocker, U0126, an inhibitor of phospholipase A(2), and a protein phosphatase inhibitor also blocked the effect of dopamine on ENaC P-o. Finally, since the cAMP-EPAC-Rap1 pathway also activates DARPP32 (32-kDa dopamine response protein phosphatase), we confirmed that dopamine phosphorylates DARPP32, and okadaic acid, which blocks phosphatases (DARPP32), also blocks dopamine's effect. In summary, dopamine increases ENaC activity by a cAMP-mediated alternative signaling pathway involving EPAC and Rap1, signaling molecules usually associated with growth-factor-activated receptors.
引用
收藏
页码:L710 / L722
页数:13
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