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Abstract: 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 δ subunit (ENaCδ) 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 ENaCδ 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 (α, β, and γ) 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 ENaCδβγα complex generated an amiloride-sensitive inward current at the holding potential of −60 mV. The ENaCδβγα 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, ENaCδ is a candidate molecule for pH sensing in the gastrointestinal system in humans, providing a novel therapeutic target for gastro-oesophageal reflux disease. [Copyright &y& Elsevier]