Epithelial Na+ channel δ subunit is an acid sensor in the human oesophagus

Gastro-oesophageal reflux disease is caused by the reflux of gastric contents into the oesophagus, and thus the oesophageal lumen is damaged by gastric acid. The acid sensor involved in oesophageal epithelial defense is still unclear. Recently, we described that the epithelial Na+ channel 8 subunit (ENaC delta) is a candidate molecule for a pH sensor in the human brain. Here, using reverse transcription-polymerase chain reaction and in situ hybridization methods, we showed that the proton-sensitive ENaC delta was strongly expressed in the epithelial layer of the human oesophagus, representative peripheral tissue that can be exposed to an acidic environment. Other ENaC subunits (alpha, beta, and gamma) were also localized there. Based on the expression pattern, human oesophageal ENaC complex was mimicked in the Xenopus oocyte expression system and the response to acidic pH was recorded using a two-electrode voltage-clamp technique. The human oesophageal-mimicking ENaC delta beta alpha complex generated an amiloride-sensitive inward current at the holding potential of -60 mV. The ENaC delta beta alpha current was significantly activated by acidic pH (pH 4.0), approximately equal to the luminal value when gastric acid refluxes into the oesophagus. In conclusion, ENaC delta is a candidate molecule for pH sensing in the gastrointestinal system in humans, providing a novel therapeutic target for gastro-oesophageal reflux disease. (c) 2008 Elsevier B.V. All rights reserved.