Gardos potassium channel amplifies PIEZO1-TMEM16F coupling in red blood cells
In red blood cells (RBCs), the mechanosensitive channel PIEZO1 provides an upstream Ca 2+ signal that activates TMEM16F, a Ca 2+ -activated phospholipid scramblase (CaPLSase) responsible for phosphatidylserine (PS) externalization. However, limited PIEZO1-mediated Ca²⁺ entry and the relatively low Ca 2+ sensitivity of TMEM16F suggest the need for signal amplification. Here, we identify the Gardos (KCNN4) Ca 2+ -activated K⁺ channel as a critical amplifier of the PIEZO1-TMEM16F axis. Gardos activation induces membrane hyperpolarization, thereby increasing the driving force for Ca 2+ entry and enhancing TMEM16F activation and phospholipid scrambling. Gardos-mediated amplification also contributes to excessive PS externalization in sickle cell disease (SCD) and hereditary xerocytosis (HX) RBCs, and functional disruption of Gardos-mediated K + efflux attenuates this response. These findings demonstrate Gardos as a critical amplifier of RBC mechanotransduction and highlight Gardos as a potential therapeutic target for mitigating pathogenic PS exposure. Gardos amplifies PIEZO1-mediated Ca²⁺ influx to promote TMEM16F-dependent phosphatidylserine exposure in healthy and diseased RBCs. Unexpected effects of some Gardos inhibitors may complicate the use in hematologic diseases.
