Intracellular H+ regulates the α-subunit of ENaC, the epithelial Na+ channel

Michael L. Chalfant, Jerod S. Denton, Bakhram K. Berdiev, Iskander I. Ismailov, Dale J. Benos, Bruce A. Stanton

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61 Citations (Scopus)


Protons regulate electrogenic sodium absorption in a variety of epithelia, including the cortical collecting duct, frog skin, and urinary bladder. Recently, three subunits (α, β, γ) coding for the epithelial sodium channel (ENaC) were cloned. However, it is not known whether pH regulates Na+ channels directly by interacting with one of the three ENaC subunits or indirectly by interacting with a regulatory protein. As a first step to identifying the molecular mechanisms of proton-mediated regulation of apical membrane Na+ permeability in epithelia, we examined the effect of pH on the biophysical properties of ENaC. To this end, we expressed various combinations of α-, β-, and γ-subunits of ENaC in Xenopus oocytes and studied ENaC currents by the two-electrode voltage-clamp and patch-clamp techniques. In addition, the effect of pH on the α-ENaC subunit was examined in planar lipid bilayers. We report that α, β, γ-ENaC currents were regulated by changes in intracellular pH (pH1) but not by changes in extracellular pH (pH0). Acidification reduced and alkalization increased channel activity by a voltage-independent mechanisms. Moreover, a reduction of pH1 reduced single-channel open probability, reduced single-channel open time, and increased single-channel closed time without altering single- channel conductance. Acidification of the cytoplasmic solution also inhibited α,β-ENaC, and α,γ-ENaC, and α-ENaC currents. We conclude that pH1 but not pH0 regulates ENaC and that the α-ENaC subunit is regulated directly by pH1.

Original languageEnglish
Pages (from-to)C477-C486
JournalAmerican Journal of Physiology - Cell Physiology
Issue number2 45-2
Publication statusPublished - 1999


  • Amiloride
  • Cortical collecting duct
  • Hydrogen ion
  • Patch clamp
  • Xenopus oocyte

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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