Selective serotonin reuptake inhibitors facilitate ANO6 (TMEM16F) current activation and phosphatidylserine exposure

Anoctamin 6 (ANO6) is a member of the recently identified TMEM16/anoctamin protein family comprising Ca²⁺-activated Cl⁻ channels that generate outward-rectifying ionic currents in response to intracellular Ca²⁺ increase. ANO6 is also essential for Ca²⁺-dependent phospholipid scrambling required for blood coagulation. Selective serotonin reuptake inhibitors (SSRIs)—fluoxetine, sertraline, and paroxetine—that are used for the treatment of major depressive disorders can increase the risk of upper gastrointestinal bleeding after chronic treatment. However, at the earlier stage of intake, which is 1–7 days after the treatment, the possibility of blood coagulation might also increase, but transiently. Therefore, in this study, we investigated whether therapeutic SSRI concentrations affected the Cl⁻ current or phospholipid scrambling activity of ANO6 by assessing ANO6 currents (I_ANO6), phosphatidylserine (PS) exposure, and platelet aggregation. In the whole-cell patch mode, SSRIs facilitated Ca²⁺-dependent activation of I_ANO6 in ANO6-transfected cells, as evidenced by a significant decrease in the delay of I_ANO6 generation. On the other hand, in the inside-out patch clamp configuration, SSRIs showed an inhibitory effect on ANO6 currents, suggesting that SSRIs activate ANO6 via an indirect mechanism in intact cells. SSRIs also facilitated Ca²⁺-dependent PS exposure and α-thrombin-induced platelet aggregation. These results indicate that SSRIs at clinically relevant concentrations promote Ca²⁺-dependent activation of ANO6, which may have potential clinical implications such as the underlying mechanism of SSRI-induced adverse drug reactions.