Sphingomyelinase Disables Inactivation in Endogenous PIEZO1 Channels

被引：59

作者：

Shi, Jian ^{[1
]}

Hyman, Adam J. ^{[1
]}

De Vecchis, Dario ^{[1
]}

Chong, Jiehan ^{[1
]}

Lichtenstein, Laeticia ^{[1
]}

Futers, T. Simon ^{[1
]}

Rouahi, Myriam ^{[3
,4
]}

Salvayre, Anne Negre ^{[3
,4
]}

Auge, Nathalie ^{[3
,4
]}

Kalli, Antreas C. ^{[1
,2
]}

Beech, David J. ^{[1
]}

机构：

[1] Univ Leeds, Sch Med, Leeds Inst Cardiovasc & Metab Med, Leeds LS2 9JT, W Yorkshire, England

[2] Univ Leeds, Astbury Ctr Struct Mol Biol, Leeds LS2 9JT, W Yorkshire, England

[3] INSERM, U1048, F-31432 Toulouse 4, France

[4] Univ Paul Sabatier, F-31432 Toulouse 4, France

来源：

CELL REPORTS | 2020年 / 33卷 / 01期

基金：

英国惠康基金; 英国生物技术与生命科学研究理事会;

关键词：

ION CHANNELS; NEUTRAL SPHINGOMYELINASE; MOLECULAR-DYNAMICS; INHIBITOR; HEALTH; FLOW;

D O I：

10.1016/j.celrep.2020.108225

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：16

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