Shi, J orcid.org/0000-0003-2179-8579, Hyman, AJ orcid.org/0000-0003-0874-6678, De Vecchis, D orcid.org/0000-0002-7732-5095 et al. (8 more authors) (2020) Sphingomyelinase Disables Inactivation in Endogenous PIEZO1 Channels. Cell Reports, 33 (1). 108225. ISSN 2211-1247
Abstract
Endogenous PIEZO1 channels of native endothelium lack the hallmark inactivation often seen when these channels are overexpressed in cell lines. Because prior work showed that the force of shear stress activates sphingomyelinase in endothelium, we considered if sphingomyelinase is relevant to endogenous PIEZO1. Patch clamping was used to quantify PIEZO1-mediated signals in freshly isolated murine endothelium exposed to the mechanical forces caused by shear stress and membrane stretch. Neutral sphingomyelinase inhibitors and genetic disruption of sphingomyelin phosphodiesterase 3 (SMPD3) cause PIEZO1 to switch to profoundly inactivating behavior. Ceramide (a key product of SMPD3) rescues non-inactivating channel behavior. Its co-product, phosphoryl choline, has no effect. In contrast to ceramide, sphingomyelin (the SMPD3 substrate) does not affect inactivation but alters channel force sensitivity. The data suggest that sphingomyelinase activity, ceramide, and sphingomyelin are determinants of native PIEZO gating that enable sustained activity.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020 The Authors. This is an open access article under the terms of the Creative Commons Attribution License (CC-BY) (https://creativecommons.org/licenses/by/4.0/) |
Keywords: | PIEZO1; inactivation; endothelium; sphingomyelinase; SMPD3; ceramide; sphingomyelin; mechanically activated channel; molecular dynamics; simualtions |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) |
Funding Information: | Funder Grant number British Heart Foundation FS/17/2/32559 British Heart Foundation RG/17/11/33042 MRC (Medical Research Council) MR/R01745X/1 Wellcome Trust 110044/Z/15/Z |
Depositing User: | Symplectic Publications |
Date Deposited: | 16 Sep 2020 15:08 |
Last Modified: | 08 Jan 2025 12:24 |
Status: | Published |
Publisher: | Cell Press |
Identification Number: | 10.1016/j.celrep.2020.108225 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:165506 |