The human bile acid-sensitive ion channel hBASIC is a member of the DEG/ENaC gene family. According to the main site of expression, the intestinal tract, hBASIC was initially named hINaC (human intestinal Na+ channel), BASIC from mouse and rat were named BLINaC (brain liver intestine Na+ channel) as they were additionally found in brain and liver. Based on their sensitivity for bile acids, INaC/BLINaC were recently renamed BASIC. Furthermore immunohistochemical data suggest that the channel is strongly expressed in cholangiocytes, the epithelial cells of the bile ducts. Despite the high degree of sequence identity between hBASIC and its orthologs from mouse and rat, the pharmacological and electrophysiological features vary drastically between these channels. While mBASIC is a constitutively open channel, hBASIC and rBASIC are almost completely blocked by physiological concentrations of extracellular Ca2+. Consequently removal of Ca2+ opens the channels. rBASIC is strongly activated by the bile acids chenodeoxycholic acid (CDCA) and hyodeoxycholic acid (HDCA), which are both present in murine bile. When co-applied, CDCA and HDCA cause a synergistic activation of the channel. In contrast, hBASIC is strongly activated by CDCA but only weakly by HDCA and co-application caused no synergistic effect. However, only CDCA but not HDCA is present in human bile. Therefore we extended our study to bile acids present in the human bile acid pool and applied the most common human bile acids CDCA, cholic acid (CA) and deoxycholic acid (DCA) individually and in combination. Interestingly DCA activates hBASIC as potently as CDCA and a synergistic activation could be observed when co-applied. Additional removal of extracellular Ca2+ during the application of bile acids leads to increased current amplitudes without changing the amplitude relationship. Thus, removal of extracellular Ca2+ and bile acids displayed a synergistic effect on hBASIC activity. In summary human and rat BASIC differ in their sensitivity for different bile acids. Furthermore they show a preference for bile acids present in the respective species-specific bile acid pool, supporting the hypothesis that BASICs may have co-evolved to match the bile acid prevalence of different species.