Regulation of the epithelial Na+ channel by extracellular acidification

The effect of extracellular acidification was tested on the native epithelial Na(+) channel (ENaC) in A6 epithelia and on the cloned ENaC expressed in Xenopus oocytes. Channel activity was determined utilizing blocker-induced fluctuation analysis in A6 epithelia and dual electrode voltage clamp in oocytes. In A6 cells, a decrease of extracellular pH (pH(o)) from 7.4 to 6.4 caused a slow stimulation of the amiloride-sensitive short-circuit current (I(Na)) by 68.4 +/- 11% (n = 9) at 60 min. This increase of I(Na) was attributed to an increase of open channel and total channel (N(T)) densities. Similar changes were observed with pH(o) 5.4. The effects of pH(o) were blocked by buffering intracellular Ca(2+) with 5 microM 1, 2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid. In oocytes, pH(o) 6.4 elicited a small transient increase of the slope conductance of the cloned ENaC (11.4 +/- 2.2% at 2 min) followed by a decrease to 83.7 +/- 11.7% of control at 60 min (n = 6). Thus small decreases of pH(o) stimulate the native ENaC by increasing N(T) but do not appreciably affect ENaC expressed in Xenopus oocytes. These effects are distinct from those observed with decreasing intracellular pH with permeant buffers that are known to inhibit ENaC.