Anion and Cation Permeability of the Mouse TMEM16F Calcium-Activated Channel

TMEM16F is involved in several physiological processes, such as blood coagulation, bone development and virus infections. This protein acts both as a Ca(2+)-dependent phospholipid scramblase and a Ca(2+)-activated ion channel but several studies have reported conflicting results about the ion selectivity of the TMEM16F-mediated current. Here, we have performed a detailed side-by-side comparison of the ion selectivity of TMEM16F using the whole-cell and inside-out excised patch configurations to directly compare the results. In inside-out configuration, Ca(2+)-dependent activation was fast and the TMEM16F-mediated current was activated in a few milliseconds, while in whole-cell recordings full activation required several minutes. We determined the relative permeability between Na(+) and Cl¯ (P(Na)/P(Cl)) using the dilution method in both configurations. The TMEM16F-mediated current was highly nonselective, but there were differences depending on the configuration of the recordings. In whole-cell recordings, P(Na)/P(Cl) was approximately 0.5, indicating a slight preference for Cl¯ permeation. In contrast, in inside-out experiments the TMEM16F channel showed a higher permeability for Na(+) with P(Na)/P(Cl) reaching 3.7. Our results demonstrate that the time dependence of Ca(2+) activation and the ion selectivity of TMEM16F depend on the recording configuration.