Normal CFTR Activity and Reversed Skin Potentials in Pseudohypoaldosteronism.
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.
Department of Pediatrics, UCSD School of Medicine, University of California, San Diego, La-Jolla, 92093-0831, USA. mmr@ ucsd.edu
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Reddy
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Wang
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Gottschalk
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Jones
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Quinton
D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D053503:Epithelial Sodium Channels; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D011546:Pseudohypoaldosteronism / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013542:Sweat / Q000378:metabolism; D013545:Sweat Glands / Q000378:metabolism*
D053503:Epithelial Sodium Channels; D015222:Sodium Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator