Abstract

The brain liver intestine Na⁺ channel (BLINaC) is a member of the degenerin/epithelial Na⁺ channel gene family of unknown function. Elucidation of the physiological function of BLINaC would benefit greatly from pharmacological tools that specifically affect BLINaC activity. Guided by the close molecular relation of BLINaC to acid-sensing ion channels, we discovered in this study that rat BLINaC (rBLINaC) and mouse BLINaC are inhibited by micromolar concentrations of diarylamidines and nafamostat, similar to acid-sensing ion channels. Inhibition was voltage-dependent, suggesting pore block as the mechanism of inhibition. Furthermore, we identified the fenamate flufenamic acid and related compounds as agonists of rBLINaC. Application of millimolar concentrations of flufenamic acid to rBLINaC induced a robust, Na⁺-selective current, which was blocked partially by amiloride. The identification of an artificial agonist of rBLINaC supports the hypothesis that rBLINaC is opened by an unknown physiological ligand. Inhibition by diarylamidines and activation by fenamates define a unique pharmacological profile for BLINaC, which will be useful to unravel the physiological function of this ion channel.