The amiloride-sensitive epithelial Na+ channel regulates Na+ homeostasis in cells. Recently, we described that the delta-subunit is a candidate molecule for a pH sensor in the human brain. Here, an N-terminal spliced variant of the delta-subunit is cloned from human brain, and designated as the delta 2-subunit, which is expressed with the original delta-subunit (delta 1-subunit) at the same level in the human brain. Functional analyses revealed that the physiological and pharmacological properties (interaction with accessory beta gamma-subunits, activation by acidic pH, amiloride sensitivity) of the delta 2-subunit were similar to those of the delta 1-subunit. In conclusion, the activities of both subunits may be involved in the mechanism underlying pH sensing in the human brain. (c) 2006 Elsevier Inc. All rights reserved.