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1 Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
* To whom correspondence should be addressed. E-mail: stockand{at}uthscsa.edu.
Epidermal growth factor (EGF) decreases Na+ reabsorption across distal nephron epithelia. Activity of the epithelial Na+ channel (ENaC) is limiting for Na+ transport in this portion of the nephron. Abnormal ENaC activity and EGF signaling are both associated with polycystic kidney disease (PKD) localized to the distal nephron. We tested here whether EGF and other ligands for receptor tyrosine kinases (RTK) decrease ENaC activity. EGF markedly and quickly decreased ENaC activity. The RTK inhibitor erbstatin blocked EGF actions on ENaC and when added alone increased channel activity uncovering basal suppression by endogenous RTK. The protein tyrosine phosphatase (PTP) inhibitor vanadate, similar to EGF, decreased ENaC activity. Growth factors and vanadate decreased ENaC activity by decreasing open probability. ENaC was not phosphorylated in response to EGF indicating that intermediary proteins transduce the inhibitory signal from EGFR to ENaC. We find that neither MAPK 1/2 nor c-Src are signaling intermediaries between EGFR and ENaC. Inhibition of ENaC paralleled decreases in plasma membrane phosphatidylinositol 4,5-bisphosphate levels (PtdIns(4,5)P2) and was abolished by clamping PtdIns(4,5)P2. We conclude that EGF and other ligands for RTK decrease ENaC open probability by decreasing membrane PtdIns(4,5)P2 levels.
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