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bioRxiv · 10.1101/2021.12.11.472241

Functional coupling between TRPV4 channel and TMEM16F modulates human trophoblast fusion

Zhang, Y.·Liang, P.·Shan, K. Z.·Feng, L.·Chen, Y.·Liedtke, W.·Yang, H.
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Abstract

TMEM16F, a Ca2+-activated phospholipid scramblase (CaPLSase), is critical for placental trophoblast syncytialization, HIV infection, and SARS-CoV2-mediated syncytialization. How TMEM16F is activated during cell fusion is unclear. Here, we used trophoblasts as a model for cell fusion and demonstrated that Ca2+ influx through Ca2+ permeable transient receptor potential vanilloid channel TRPV4 is critical for TMEM16F activation and subsequent human trophoblast fusion. GSK1016790A, a TRPV4 specific agonist, robustly activates TMEM16F in trophoblasts. Patch-clamp electrophysiology demonstrated that TRPV4 and TMEM16F are functionally coupled within Ca2+ microdomains in human trophoblasts. Pharmacological inhibition or gene silencing of TRPV4 hindered TMEM16F activation and subsequent trophoblast syncytialization. Our study uncovers the functional expression of TRPV4 and a physiological activation mechanism of TMEM16F in human trophoblasts, thus providing us with novel strategies to regulate CaPLSase activity as a critical checkpoint of physiologically- and disease-relevant cell fusion events.

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Zhang, Y., Liang, P., Shan, K. Z., Feng, L., Chen, Y., Liedtke, W., Yang, H.. 2021-12-12. Functional coupling between TRPV4 channel and TMEM16F modulates human trophoblast fusion. https://doi.org/10.1101/2021.12.11.472241

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