Biology subjects

Delahunty, M.

Publications and source records attributed to Delahunty, M..

3 recordsLinked to original sources

bioRxiv2026

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

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

physiology↗

bioRxiv2026

Cannabidiol Inhibits PIEZO Channels to Mitigate Red Blood Disorders

Hyperactivity of the mechanosensitive ion channel PIEZO1 promotes pathologic Ca{superscript 2} overload in red blood cells (RBCs), driving dehydration, TMEM16F-dependent phosphatidylserine (PS) exposure, microparticle shedding, and increased thrombotic and vaso-occlusive risks in hereditary xerocytosis (HX) and sickle cell disease (SCD). However, clinically deployable PIEZO inhibitors to treat these blood disorders are lacking. Here we report that cannabidiol (CBD), a non-psychoactive cannabinoid commonly used in SCD patients for pain management, inhibits PIEZO1 activity and restores aberrant mechanotransduction in HX and SCD RBCs. Micromolar concentrations of CBD blocks PIEZO1 currents and suppresses PIEZO1-mediate Ca{superscript 2} entry. In HX and SCD RBCs, CBD attenuates PIEZO1-TMEM16F coupling, thereby reducing PS exposure, microparticle release, thrombin generation, RBC-endothelium adhesion, and sickling. Beyond RBCs, CBD also blocks PIEZO2 currents and PIEZO2-dependent mechanical sensation in mice, suggesting broader effects of CBD-mediated PIEZO inhibition on nociceptive functions. Together, our findings identify CBD as a potent PIEZO inhibitor that restores calcium and membrane homeostasis, supporting the repurposing of CBD or the development of CBD-derived, PIEZO-selective analogs as a promising disease-modifying strategy for SCD, HX, and other PIEZO-mediated mechanosensing disorders. HighlightsO_LICBD inhibits PIEZO channels and disrupts the PIEZO1-TMEM16F axis in diseased RBCs C_LIO_LICBD shows a therapeutic window to prevent PS exposure and translational promise for HX and SCD C_LI

pharmacology and toxicology↗

bioRxiv2025

Targeting PIEZO1-TMEM16F Coupling to Mitigate Sickle Cell Disease Complications

A deeper understanding of sickle cell disease (SCD) pathophysiology is critical for identifying novel therapeutic targets. A hallmark of SCD is abnormal phosphatidylserine (PS) exposure on sickle red blood cells (RBCs), which contributes to anemia, thrombosis, and vaso-occlusive crises (VOC). However, the mechanisms underlying this excessive PS exposure remain unclear. Here, we identify TMEM16F, a Ca2+-activated lipid scramblase, as a key mediator of PS exposure downstream of Ca2+ influx through the mechanosensitive channel PIEZO1 in sickle RBCs. Electrophysiology, imaging and flow cytometry reveal that deoxygenation-induced sickling promotes PIEZO1 activation, triggering Ca2+ entry, TMEM16F activation, and PS exposure. This cascade enhances PS+ microparticle release, thrombin generation, and RBC adhesion to endothelial cells. Notably, partial PIEZO1 inhibition with benzbromarone, an anti-gout drug, suppresses these changes. Our findings thus define a previously unrecognized mechanotransduction pathway in sickle RBCs and propose a unique therapeutic strategy to mitigate hypercoagulability and vaso-occlusion associated with SCD. Brief SummaryEnhanced PIEZO1 activation in sickle red blood cells promotes TMEM16F scramblase-mediated phosphatidylserine exposure and subsequent sickle cell disease complications. Disrupting this coupling presents a potential therapeutic strategy.

physiology↗