Biophys J, December 1999, p. 3043-3051, Vol. 77, No. 6

Inhibition of Epithelial Sodium Channels by External Protons Indicates That the Second Hydrophobic Domain Contains Structural Elements for Closing the Pore

Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520-8026 USA

We have examined the effect of extracellular protons on the activity of epithelial sodium channels (ENaCs). We found that channels, but not or channels, are inhibited by low extracellular pH. External protons induced short and long closed states that markedly decreased the open probability of channels. External protons did not change the single-channel conductance or amiloride binding. Analysis of the proton-induced changes on the kinetics of single channels indicates that at least two protons sequentially bind to the extracellular domain at sites that are not in the ion pathway. Conformational changes induced by protonation of those sites are transmitted to the second hydrophobic domain (M2) of the subunits to induce closure of the pore. The results suggest that elements located in the carboxy-terminal half of M2 participate in the gating mechanism of ENaCs.

Biophys J, December 1999, p. 3043-3051, Vol. 77, No. 6
© 1999 by the Biophysical Society   0006-3495/99/12/3043/09  $2.00

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