Sphingomyelinase Disables Inactivation in Endogenous PIEZO1 Channels
| Autor: | Laeticia Lichtenstein, Jian Shi, Myriam Rouahi, Nathalie Augé, Jiehan Chong, Adam J. Hyman, David J. Beech, Dario De Vecchis, T. Simon Futers, Antreas C. Kalli, Anne Negre Salvayre |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Ceramide Endothelium endothelium Endogeny Gating Sphingomyelin phosphodiesterase General Biochemistry Genetics and Molecular Biology Ion Channels Article sphingomyelin 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine medicine simualtions Animals Humans mechanically activated channel Patch clamp inactivation ceramide sphingomyelinase lcsh:QH301-705.5 SMPD3 PIEZO1 molecular dynamics Cell biology 030104 developmental biology medicine.anatomical_structure Sphingomyelin Phosphodiesterase chemistry lcsh:Biology (General) Sphingomyelin 030217 neurology & neurosurgery |
| Zdroj: | Cell Reports, Vol 33, Iss 1, Pp 108225-(2020) Cell Reports |
| ISSN: | 2211-1247 |
| Popis: | Summary 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. Graphical Abstract Highlights • SMPD3 sphingomyelinase enables long-lasting PIEZO1 activity in response to force • Ceramide, a key lipid product of SMPD3, promotes long-lasting activity • Sphingomyelin, the SMPD3 substrate, does not affect the duration of activity • Sphingomyelin alters PIEZO1 force sensitivity The vascular endothelial response to blood flow involves sustained activation of mechanically activated PIEZO1 channels; yet, PIEZO1 has an intrinsic rapid inactivation gate that should prevent long-lasting activity. Shi et al. show that the gate is disabled in the endothelium by sphingomyelinase that produces ceramide, thus enabling physiologically appropriate responses. |
| Databáze: | OpenAIRE |
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