Normal CFTR Activity and Reversed Skin Potentials in Pseudohypoaldosteronism

J Membr Biol. 2005 Feb;203(3):151-9. doi: 10.1007/s00232-005-0740-0.

Abstract

Cystic fibrosis (CF) transmembrane conductance regulator (CFTR) Cl(-) channel function is required for activating amiloride-sensitive epithelial Na(+) channels (ENaC) in salt-absorbing human sweat duct. It is unclear whether ENaC channel function is also required for CFTR activation. The dysfunctional ENaC mutations in type-1 pseudohypoaldosteronism (PHA-1) provided a good opportunity to study this phenomenon of ion channel interaction between CFTR and ENaC. The PHA-1 ducts completely lacked spontaneous ENaC conductance (gENaC). In contrast, the normal ducts showed large spontaneous gENaC (46 +/- 10 ms, mean +/- SE: ). After permeabilization of the basolateral membrane with alpha-toxin, cAMP + ATP activation of CFTR Cl(-) conductance (gCFTR) or alkalinization of cytosolic pH (6.8 to 8.5) stimulated gENaC of normal but not PHA-1 ducts. In contrast, both spontaneous gCFTR in intact ducts and (cAMP + ATP)-activated gCFTR of permeabilized ducts appeared to be similar in normal and PHA-1 subjects. Lack of gENaC completely blocked salt absorption and caused dramatic reversal of skin potentials associated with pilocarpine-induced sweat secretion from significantly negative in normal subjects (-13 +/- 7.0 mV) to significantly positive (+22 +/- 11.0 mV) in PHA-1 patients. We conclude that virtual lack of ENaC in PHA-1 ducts had little effect on CFTR activity and that the positive skin potentials could potentially serve as a diagnostic tool to identify type-1 pseudohypoaldosteronism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Epithelial Sodium Channels
  • Membrane Potentials / genetics
  • Membrane Potentials / physiology
  • Pseudohypoaldosteronism / diagnosis
  • Pseudohypoaldosteronism / genetics
  • Pseudohypoaldosteronism / metabolism*
  • Sodium Channels / genetics
  • Sodium Channels / metabolism*
  • Sweat / metabolism
  • Sweat Glands / metabolism*

Substances

  • Epithelial Sodium Channels
  • Sodium Channels
  • Cystic Fibrosis Transmembrane Conductance Regulator