Liddle's syndrome mutations disrupt cAMP-mediated translocation of the epithelial Na(+) channel to the cell surface.
The epithelial Na(+) channel (ENaC) plays a critical role in Na(+) absorption, and mutations in this channel cause diseases of Na(+) homeostasis, including a genetic form of hypertension (Liddle's syndrome). To investigate cAMP-mediated stimulation of ENaC, alpha, beta, and gammaENaC were coexpressed in Fischer rat thyroid epithelia to generate apical Na(+) channels and transepithelial Na(+) current. cAMP agonists stimulated Na(+) current by 70%. Following covalent modification of cysteines introduced into ENaC, cAMP increased the rate of appearance of unmodified channels at the cell surface. In addition, cAMP increased the fluorescent labeling of ENaC at the apical cell surface. Inhibition of vesicle trafficking by incubating epithelia at 15 degrees C prevented the cAMP-mediated stimulation of ENaC. These results suggest that cAMP stimulates Na(+) absorption in part by increasing translocation of ENaC to the cell surface. Stimulation of ENaC by cAMP was dependent on a sequence (PPPXY) in the COOH terminus of each subunit. This sequence is the target for mutations that cause Liddle's syndrome, suggesting that cAMP-mediated translocation of ENaC to the cell surface is defective in this genetic form of hypertension.
Snyder
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PM
200K Eckstein Medical Research Building, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA. psnyder@blue.weeg.uiowa.edu
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000502:physiology; D004848:Epithelium / Q000378:metabolism; D006973:Hypertension / Q000235:genetics*; D008698:Mesylates / Q000494:pharmacology; D009154:Mutation; D051381:Rats; D011916:Rats, Inbred F344; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology
D008698:Mesylates; D015222:Sodium Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C109154:(2-(trimethylammonium)ethyl)methanethiosulfonate; D012964:Sodium; D000242:Cyclic AMP; D015056:1-Methyl-3-isobutylxanthine