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Enantiomeric A? peptides inhibit the fluid shear stress response of PIEZO1.

ABSTRACT: Traumatic brain injury (TBI) elevates Abeta (A?) peptides in the brain and cerebral spinal fluid. A? peptides are amphipathic molecules that can modulate membrane mechanics. Because the mechanosensitive cation channel PIEZO1 is gated by membrane tension and curvature, it prompted us to test the effects of A? on PIEZO1. Using precision fluid shear stress as a stimulus, we found that A? monomers inhibit PIEZO1 at femtomolar to picomolar concentrations. The A? oligomers proved much less potent. The effect of A?s on Piezo gating did not involve peptide-protein interactions since the D and L enantiomers had similar effects. Incubating a fluorescent derivative of A? and a fluorescently tagged PIEZO1, we showed that A? can colocalize with PIEZO1, suggesting that they both had an affinity for particular regions of the bilayer. To better understand the PIEZO1 inhibitory effects of A?, we examined their effect on wound healing. We observed that over-expression of PIEZO1 in HEK293 cells increased cell migration velocity ~10-fold, and both enantiomeric A? peptides and GsMTx4 independently inhibited migration, demonstrating involvement of PIEZO1 in cell motility. As part of the motility study we examined the correlation of PIEZO1 function with tension in the cytoskeleton using a genetically encoded fluorescent stress probe. A? peptides increased resting stress in F-actin, and is correlated with A? block of PIEZO1-mediated Ca²⁺ influx. A? inhibition of PIEZO1 in the absence of stereospecific peptide-protein interactions shows that A? peptides modulate both cell membrane and cytoskeletal mechanics to control PIEZO1-triggered Ca²⁺ influx.

SUBMITTER: Maneshi MM

PROVIDER: S-EPMC6155315 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Enantiomeric Aβ peptides inhibit the fluid shear stress response of PIEZO1.

Maneshi Mohammad M MM Ziegler Lynn L Sachs Frederick F Hua Susan Z SZ Gottlieb Philip A PA

Scientific reports 20180924 1

Traumatic brain injury (TBI) elevates Abeta (Aβ) peptides in the brain and cerebral spinal fluid. Aβ peptides are amphipathic molecules that can modulate membrane mechanics. Because the mechanosensitive cation channel PIEZO1 is gated by membrane tension and curvature, it prompted us to test the effects of Aβ on PIEZO1. Using precision fluid shear stress as a stimulus, we found that Aβ monomers inhibit PIEZO1 at femtomolar to picomolar concentrations. The Aβ oligomers proved much less potent. The ...[more]

PMID: 30250223

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Project description:Blood flow produces mechanical frictional forces, parallel to the blood flow exerted on the endothelial wall of the vessel, the so-called wall shear stress (WSS). WSS sensing is associated with several vascular pathologies, but it is first a physiological phenomenon. Endothelial cell sensitivity to WSS is involved in several developmental and physiological vascular processes such as angiogenesis and vascular morphogenesis, vascular remodeling, and vascular tone. Local conditions of blood flow determine the characteristics of WSS, i.e., intensity, direction, pulsatility, sensed by the endothelial cells that, through their effect of the vascular network, impact WSS. All these processes generate a local-global retroactive loop that determines the ability of the vascular system to ensure the perfusion of the tissues. In order to account for the physiological role of WSS, the so-called shear stress set point theory has been proposed, according to which WSS sensing acts locally on vessel remodeling so that WSS is maintained close to a set point value, with local and distant effects of vascular blood flow. The aim of this article is (1) to review the existing literature on WSS sensing involvement on the behavior of endothelial cells and its short-term (vasoreactivity) and long-term (vascular morphogenesis and remodeling) effects on vascular functioning in physiological condition; (2) to present the various hypotheses about WSS sensors and analyze the conceptual background of these representations, in particular the concept of tensional prestress or biotensegrity; and (3) to analyze the relevance, explanatory value, and limitations of the WSS set point theory, that should be viewed as dynamical, and not algorithmic, processes, acting in a self-organized way. We conclude that this dynamic set point theory and the biotensegrity concept provide a relevant explanatory framework to analyze the physiological mechanisms of WSS sensing and their possible shift toward pathological situations.

Dataset Information

Enantiomeric A? peptides inhibit the fluid shear stress response of PIEZO1.

Publications

Enantiomeric Aβ peptides inhibit the fluid shear stress response of PIEZO1.

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