The physiological function of members of the DEG/ENaC family of ion channels ranges from Na+-reabsorption over pH-sensing and neuronal transmission to mechanosensation and the sensation of taste. As diverse as their physiological functions are their modes of activation. Constitutively active channels like the epithelial Na+ channel (ENaC) and proton-sensitive channels like the acid-sensing ion channels (ASICs) are found in this ion channel family as well as mechanosensitive channels like MEC-4 and peptide-gated channels like Hydra Na+ channels (HyNaCs). The bile acid-sensitive ion channel (BASIC) adds another layer of diversity to the DEG/ENaC family. It is expressed in cholangiocytes, the epithelial cells lining the bile ducts and strongly activated by bile acids. Both, physiological function and the mode of activation are not known so far. Bile acids are negatively charged, amphiphilic derivatives of cholesterol that affect structure, curvature and fluidity of membranes. They could activate BASIC either indirectly by interfering with the membrane or directly in a ligand-like manner by binding to the channel. We addressed this question by employing a pharmacological approach and used molecules, which are known to affect biological membranes. Crenating agents like trinitrophenol (TNP) and cup-forming molecules like chlorpromazine (CPZ) were applied to Xenopus oocytes expressing BASIC or co-applied with bile acids. Interestingly, the anionic TNP had a stimulatory effect when co-applied with bile acids or when applied alone at millimolar concentrations while the cationic CPZ displayed an inhibitory effect when co-applied with bile acids. Other membrane active substances like anionic or cationic tensides also affected the activity of BASIC. These data point towards a mechanism of activation, where the membrane is modulated and BASIC functions as a sensor for this modulation. In addition to the pharmacological approach we are using a chimeric approach with ASIC1a, a related but bile acid-insensitive channel, in order to define the domains of BASIC that are crucial for sensing membrane modulation induced by bile acid. Taken together our data will help to understand the events leading to the activation of the DEG/ENaC channel BASIC.