The ion channel BLINaC (Brain Liver Intestine Na⁺ Channel) is a member of the DEG/ENaC gene family. Its function is completely unknown. In rodents, it is expressed mainly in brain, liver, intestine and to a lesser extent in kidney and lung. Expression of rat BLINaC (rBLINaC) in Xenopus oocytes leads to small unselective currents that are only weakly sensitive to amiloride. We show that rBLINaC is inhibited by micromolar concentrations of extracellular Ca²⁺. Removal of Ca²⁺ leads to robust currents and increases Na⁺ selectivity of the ion pore. Strikingly, the species ortholog from mouse (mBLINaC) has an almost 250-fold lower Ca²⁺ affinity than rBLINaC, rendering mBLINaC constitutively active at physiological concentrations of extracellular Ca²⁺. In addition, mBLINaC is more selective for Na⁺ and has a 700-fold higher amiloride affinity than rBLINaC. We show that a single amino acid in the extracellular domain determines these profound species differences. Furthermore we identified the fenamate flufenamic acid (FFA) and related compounds as agonists of rBLINaC. Application of millimolar concentrations of FFA to rBLINaC expressing oocytes induces a robust, mainly Na⁺-carried current, which is partially blocked by amiloride. We also discovered that rBLINaC and mBLINaC, similar to the related acid sensing ion channels (ASIC), are inhibited by micromolar concentrations of diarylamidines and nafamostat. Collectively, our results suggest that rBLINaC is opened by an unknown ligand whereas mBLINaC is a constitutively open epithelial Na⁺ channel. Additionally we identified pharmacological tools which will enable us to unravel the physiological function of BLINaC.