Biology subjects

Wan, Y. C. S.

Publications and source records attributed to Wan, Y. C. S..

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↗

bioRxiv2023

Niclosamide potentiates TMEM16A and induces vasoconstriction

The TMEM16A calcium-activated chloride channel is a promising therapeutic target for various diseases. Niclosamide, an anthelmintic medication, has been considered as a TMEM16A inhibitor for treating asthma and chronic obstructive pulmonary disease, but was recently found to possess broad-spectrum off-target effects. Here we show that, under physiological conditions, niclosamide acutely potentiates TMEM16A without having any inhibitory effect. Our computational and functional characterizations pinpoint a putative niclosamide binding site on the extracellular side of TMEM16A. Mutations in this site attenuate the potentiation. Moreover, niclosamide potentiates endogenous TMEM16A in vascular smooth muscle cells, triggers intracellular calcium increase, and constricts the murine mesenteric artery. Our findings advise caution when considering niclosamide as a TMEM16A inhibitor to treat diseases such as asthma, COPD, and hypertension. The identification of the putative niclosamide binding site provides insights into the mechanism of TMEM16A pharmacological modulation, shining light on developing specific TMEM16A modulators to treat human diseases.

biophysics↗