Ca2+-activated Cl- channels (CaCCs) control diverse functions in several physiological processes. Recently, anoctamins (ANOs) have been identified as a family of putative Cl- channels, and ANO1 and ANO2 have been identified as essential components of the CaCCs. (1) However, the role of other members of the ANO family in generating Cl- currents by increasing the intracellular Ca2+ concentration is still a debatable matter. Recently, a study showed that ANO6 generates a small-conductance Ca2+-activated nonselective cation current. (2) In addition, ANO6 has been linked to phosphatidylserine exposure in platelet apoptosis and platelet activation. However, other studies have shown ANO6 as an essential component of the outward-rectifying Cl- channels or CaCCs. (3,4) It is therefore unclear whether ANO6 belongs to the family of CaCCs or to a family of proteins with heterogeneous functions. Serotonin-specific reuptake inhibitors (SSRIs) are widely used antidepressants that primarily act as selective serotonin reuptake inhibitors, and they inhibit various ion channels, including voltage-activated K+ channels, two-pore K+ channels, and CaCCs. In particular, ANO1 is sensitively inhibited by fluoxetine. (1) Using the whole-cell patch-clamp technique, we examined the effects of SSRIs, including fluoxetine, paroxetine, and sertraline, on cloned human ANO6 expressed in HEK293 cells. We identified that ANO6 can produce calcium-activated Cl- currents that have low sensitivity to calcium ions. (EC50: 29.9 ± 2 µM, n=5) Surprisingly, in contrast to ANO1, SSRI enhances ANO6 currents in a concentration-dependent manner. However, these mechanisms need to be elucidated in the future.