Liddle’s syndrome mutations disrupt cAMP-mediated translocation of the epithelial Na+ channel to the cell surface
AUTOR(ES)
Snyder, Peter M.
FONTE
American Society for Clinical Investigation
RESUMO
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, α, β, and γENaC 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°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.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=382584Documentos Relacionados
- Defective regulation of the epithelial Na+ channel by Nedd4 in Liddle's syndrome
- WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome.
- Requirement of subunit expression for cAMP-mediated regulation of a heart potassium channel
- cAMP-mediated inhibition of the epithelial brush border Na+/H+ exchanger, NHE3, requires an associated regulatory protein
- cAMP-mediated phosphorylation of the low-Km cAMP phosphodiesterase markedly stimulates its catalytic activity.