Sphingomyelinase disables Piezo1 channel inactivation to enable sustained response to mechanical force

Shi, J.; Hyman, A. J.; De Vecchis, D.; Chong, J.; Lichtenstein, L.; Futers, S. T.; Rouahi, M.; Negre-Salvayre, A.; Auge, N.; Kalli, A. C.; Beech, D. J.

doi:10.1101/792564

bioRxiv · 10.1101/792564

Sphingomyelinase disables Piezo1 channel inactivation to enable sustained response to mechanical force

Shi, J.·Hyman, A. J.·De Vecchis, D.·Chong, J.·Lichtenstein, L.·Futers, S. T.·Rouahi, M.·Negre-Salvayre, A.·Auge, N.·Kalli, A. C.·Beech, D. J.

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Abstract

Piezo1 channels are determinants of vascular responses to fluid flow. They importantly provide sustained response to flow, but this property contrasts with the rapid inactivation that has become a hallmark of the channels in heterologous overexpression studies. Here we reveal a mechanism by which blood vessels disable inactivation to enable sustained physiological response. Creation of a molecular model of Piezo1 channel in defined lipid membranes suggested potential modulation by sphingomyelin and its product ceramide. Biological relevance was indicated by the observation that exogenous sphingomyelinase enhanced Piezo1-mediated Ca2+ entry in cultured endothelial cells. We therefore hypothesised that endogenous sphingomyelinase suppresses channel inactivation. Remarkably, in endothelium freshly-isolated from murine artery, neutral sphingomyelinase inhibitors or genetic disruption of sphingomyelin phosphodiesterase 3 (SMPD3) caused flow- and pressure-activated Piezo1 channels to become inactivating. SMPD3 retained its ability to disable inactivation in cell-free membrane patches, providing evidence for a membrane localised effect. The data suggest that inherent inactivation of Piezo1 channels is disabled by enzymatic control of lipid environment to enable physiological response to mechanical force.

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Shi, J., Hyman, A. J., De Vecchis, D., Chong, J., Lichtenstein, L., Futers, S. T., Rouahi, M., Negre-Salvayre, A., Auge, N., Kalli, A. C., Beech, D. J.. 2019-10-04. Sphingomyelinase disables Piezo1 channel inactivation to enable sustained response to mechanical force. https://doi.org/10.1101/792564

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