Silica nanoparticles inhibit the cation channel TRPV4 in airway epithelial cells |
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Authors: | Alicia Sanchez Julio L Alvarez Kateryna Demydenko Carole Jung Yeranddy A Alpizar Julio Alvarez-Collazo Stevan M Cokic Miguel A Valverde Peter H Hoet Karel Talavera |
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Affiliation: | 1.Department of Cellular and Molecular Medicine, Laboratory of Ion Channel Research, KU Leuven; VIB Center for Brain & Disease Research,Leuven,Belgium;2.Department of Experimental and Health Sciences, Laboratory of Molecular Physiology and Channelopathies,Universitat Pompeu Fabra,Barcelona,Spain;3.KU Leuven BIOMAT, Department of Oral Health Sciences,KU Leuven & Dentistry University Hospitals Leuven,Leuven,Belgium;4.Department of Public Health and Primary Care,KU Leuven,Leuven,Belgium;5.Present address: Department of Cardiovascular Sciences, Laboratory of Experimental Cardiology,Leuven,Belgium |
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Abstract: | BackgroundSilica nanoparticles (SiNPs) have numerous beneficial properties and are extensively used in cosmetics and food industries as anti-caking, densifying and hydrophobic agents. However, the increasing exposure levels experienced by the general population and the ability of SiNPs to penetrate cells and tissues have raised concerns about possible toxic effects of this material. Although SiNPs are known to affect the function of the airway epithelium, the molecular targets of these particles remain largely unknown. Given that SiNPs interact with the plasma membrane of epithelial cells we hypothesized that they may affect the function of Transient Receptor Potential Vanilloid 4 (TRPV4), a cation-permeable channel that regulates epithelial barrier function. The main aims of this study were to evaluate the effects of SiNPs on the activation of TRPV4 and to determine whether these alter the positive modulatory action of this channel on the ciliary beat frequency in airway epithelial cells.ResultsUsing fluorometric measurements of intracellular Ca2+ concentration (Ca2+]i) we found that SiNPs inhibit activation of TRPV4 by the synthetic agonist GSK1016790A in cultured human airway epithelial cells 16HBE and in primary cultured mouse tracheobronchial epithelial cells. Inhibition of TRPV4 by SiNPs was confirmed in intracellular Ca2+ imaging and whole-cell patch-clamp experiments performed in HEK293T cells over-expressing this channel. In addition to these effects, SiNPs were found to induce a significant increase in basal Ca2+]i, but in a TRPV4-independent manner. SiNPs enhanced the activation of the capsaicin receptor TRPV1, demonstrating that these particles have a specific inhibitory action on TRPV4 activation. Finally, we found that SiNPs abrogate the increase in ciliary beat frequency induced by TRPV4 activation in mouse airway epithelial cells.ConclusionsOur results show that SiNPs inhibit TRPV4 activation, and that this effect may impair the positive modulatory action of the stimulation of this channel on the ciliary function in airway epithelial cells. These findings unveil the cation channel TRPV4 as a primary molecular target of SiNPs. |
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