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Channels (Austin)
2014 Jan 01;85:444-51. doi: 10.4161/19336950.2014.949190.
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Feedback inhibition of ENaC: acute and chronic mechanisms.
Patel AB
,
Yang L
,
Deng S
,
Palmer LG
.
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Intracellular [Na(+)] ([Na(+)]i) modulates the activity of the epithelial Na channel (ENaC) to help prevent cell swelling and regulate epithelial Na(+) transport, but the underlying mechanisms remain unclear. We show here that short-term (60-80 min) incubation of ENaC-expressing oocytes in high Na(+) results in a 75% decrease in channel activity. When the β subunit was truncated, corresponding to a gain-of-function mutation found in Liddle's syndrome, the same maneuver reduced activity by 45% despite a larger increase in [Na(+)]i. In both cases the inhibition occurred with little to no change in cell-surface expression of γENaC. Long-term incubation (18 hours) in high Na(+) reduced activity by 92% and 75% in wild-type channels and Liddle's mutant, respectively, with concomitant 70% and 52% decreases in cell-surface γENaC. In the presence of Brefeldin A to inhibit forward protein trafficking, high-Na(+) incubation decreased wt ENaC activity by 52% and 88% after 4 and 8 hour incubations, respectively. Cleaved γENaC at the cell surface had lifetimes at the surface of 6 hrs in low Na(+) and 4 hrs in high Na(+), suggesting that [Na(+)]i increased the rate of retrieval of cleaved γ ENaC by 50%. This implies that enhanced retrieval of ENaC channels at the cell surface accounts for part, but not all, of the downregulation of ENaC activity shown with chronic increases in [Na(+)]i.
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