Dataset Information

Mechanosensitive channels in lung disease.

ABSTRACT: Mechanosensitive channels (MS channels) are membrane proteins capable of responding to mechanical stress over a wide dynamic range of external mechanical stimuli. In recent years, it has been found that MS channels play an important role as "sentinels" in the process of cell sensing and response to extracellular and intracellular force signals. There is growing appreciation for mechanical activation of ion channels and their subsequent initiation of downstream signaling pathways. Members of the transient receptor potential (TRP) superfamily and Piezo channels are broadly expressed in human tissues and contribute to multiple cellular functions. Both TRP and Piezo channels are thought to play key roles in physiological homeostasis and pathophysiology of disease states including in the lung. Here, we review the current state of knowledge on the expression, regulation, and function of TRP and Piezo channels in the context of the adult lung across the age spectrum, and in lung diseases such as asthma, COPD and pulmonary fibrosis where mechanical forces likely play varied roles in the structural and functional changes characteristic of these diseases. Understanding of TRP and Piezo in the lung can provide insights into new targets for treatment of pulmonary disease.

SUBMITTER: Zheng M

PROVIDER: S-EPMC10684786 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Mechanosensitive channels in lung disease.

Zheng Mengning M Borkar Niyati A NA Yao Yang Y Ye Xianwei X Vogel Elizabeth R ER Pabelick Christina M CM Prakash Y S YS

Frontiers in physiology 20231115

Mechanosensitive channels (MS channels) are membrane proteins capable of responding to mechanical stress over a wide dynamic range of external mechanical stimuli. In recent years, it has been found that MS channels play an important role as "sentinels" in the process of cell sensing and response to extracellular and intracellular force signals. There is growing appreciation for mechanical activation of ion channels and their subsequent initiation of downstream signaling pathways. Members of the ...[more]

PMID: 38033335

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Project description:GsMTx4 is a spider venom peptide that inhibits cationic mechanosensitive channels (MSCs). It has six lysine residues that have been proposed to affect membrane binding. We synthesized six analogs with single lysine-to-glutamate substitutions and tested them against Piezo1 channels in outside-out patches and independently measured lipid binding. Four analogs had ?20% lower efficacy than the wild-type (WT) peptide. The equilibrium constants calculated from the rates of inhibition and washout did not correlate with the changes in inhibition. The lipid association strength of the WT GsMTx4 and the analogs was determined by tryptophan autofluorescence quenching and isothermal calorimetry with membrane vesicles and showed no significant differences in binding energy. Tryptophan fluorescence-quenching assays showed that both WT and analog peptides bound superficially near the lipid-water interface, although analogs penetrated deeper. Peptide-lipid association, as a function of lipid surface pressure, was investigated in Langmuir monolayers. The peptides occupied a large fraction of the expanded monolayer area, but that fraction was reduced by peptide expulsion as the pressure approached the monolayer-bilayer equivalence pressure. Analogs with compromised efficacy had pressure-area isotherms with steeper slopes in this region, suggesting tighter peptide association. The pressure-dependent redistribution of peptide between "deep" and "shallow" binding modes was supported by molecular dynamics (MD) simulations of the peptide-monolayer system under different area constraints. These data suggest a model placing GsMTx4 at the membrane surface, where it is stabilized by the lysines, and occupying a small fraction of the surface area in unstressed membranes. When applied tension reduces lateral pressure in the lipids, the peptides penetrate deeper acting as "area reservoirs" leading to partial relaxation of the outer monolayer, thereby reducing the effective magnitude of stimulus acting on the MSC gate.

Dataset Information

Mechanosensitive channels in lung disease.

Publications

Mechanosensitive channels in lung disease.

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