Functional coupling between TRPV4 channel and TMEM16F modulates human trophoblast fusion
- Duke University, United States
- Regeneron Pharmaceuticals, United States
Abstract
TMEM16F, a Ca2+-activated phospholipid scramblase (CaPLSase), is critical for placental trophoblast syncytialization, HIV infection, and SARS-CoV2-mediated syncytialization, however, how TMEM16F is activated during cell fusion is unclear. Here, using trophoblasts as a model for cell fusion, we demonstrate that Ca2+ influx through the Ca2+ permeable transient receptor potential vanilloid channel TRPV4 is critical for TMEM16F activation and plays a role in subsequent human trophoblast fusion. GSK1016790A, a TRPV4 specific agonist, robustly activates TMEM16F in trophoblasts. We also show that TRPV4 and TMEM16F are functionally coupled within Ca2+ microdomains in a human trophoblast cell line using patch clamp electrophysiology. Pharmacological inhibition or gene silencing of TRPV4 hinders TMEM16F activation and subsequent trophoblast syncytialization. Our study uncovers the functional expression of TRPV4 and one of the physiological activation mechanisms 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.
Data availability
All study data are included in the article and/or supporting information. All the numerical data can be found in the associated 'Source data' files for each figures. The MATLAB code supporting the present study is available at GitHub https://github.com/YZ299/matlabcode/blob/main/matlabcode.m.
Article and author information
Author details
Funding
National Institutes of Health (DP2GM126898)
- Huanghe Yang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#A086-21-04) of Duke University.
Human subjects: Placental tissues were collected under the Institutional Review Board approval (IRB# PRO00014627 of Duke University and XHEC-C-2018-089 of Xinhua Hospital). Informed consent was obtained following the IRBs.
Copyright
© 2022, Zhang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Functional coupling between TRPV4 channel and TMEM16F modulates human trophoblast fusion
eLife 11:e78840.
https://doi.org/10.7554/eLife.78840
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