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bioRxiv · 10.64898/2026.05.28.728404

Gardos potassium channel amplifies PIEZO1-TMEM16F coupling in red blood cells

Wan, Y. C. S.·Delahunty, M.·Lee, G. M.·Khandelwal, S.·Arepally, G. M.·Telen, M. J.·Yang, H.
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Abstract

In red blood cells (RBCs), the mechanosensitive channel PIEZO1 provides an upstream Ca2+ signal that activates TMEM16F, a Ca2+-activated phospholipid scramblase (CaPLSase) responsible for phosphatidylserine (PS) externalization. However, limited PIEZO1-mediated Ca{superscript 2} entry and the relatively low Ca2+ sensitivity of TMEM16F suggest the need for signal amplification. Here, we identify the Gardos (KCNN4) Ca2+-activated K channel as a critical amplifier of the PIEZO1-TMEM16F axis. Gardos activation induces membrane hyperpolarization, thereby increasing the driving force for Ca2+ 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. HIGHLIGHTSO_LIGardos amplifies PIEZO1-mediated Ca{superscript 2} influx to promote TMEM16F-dependent phosphatidylserine exposure in healthy and diseased RBCs. C_LIO_LIUnexpected effects of some Gardos inhibitors may complicate the use in hematologic diseases. C_LI

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Wan, Y. C. S., Delahunty, M., Lee, G. M., Khandelwal, S., Arepally, G. M., Telen, M. J., Yang, H.. 2026-05-29. Gardos potassium channel amplifies PIEZO1-TMEM16F coupling in red blood cells. https://doi.org/10.64898/2026.05.28.728404

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