The amiloride-sensitive epithelial Na+ channel (ENaC) regulates Na+ homeostasis in cells and across epithelia. Although we described that ENaC delta is a candidate molecule for a pH sensor in the human brain, the physiological and pathological roles of ENaC delta in non-neuronal tissues are still unknown. Here we show a novel physiological function of ENaC delta in peripheral tissues in humans. Expression analyses at the level of mRNA clearly revealed that ENaC delta was abundantly expressed in human epidermis and keratinocytes. In addition, ENaC delta protein was detected in there. In cultured keratinocytes, acidic stress (pH 5.0) evoked ATP release, which was significantly reduced in the presence of 100 mu M amiloride or 10 mu M benzamil. In conclusion, ENaC delta may be involved in the mechanism underlying pH sensing followed by the regulation of cell viability in the human skin. (c) 2008 Elsevier Inc. All rights reserved.