Lack of correlation between the amplitudes of TRP channel-mediated responses to weak and strong stimuli in intracellular Ca2+ imaging experiments

Alpízar, Yeranddy A.; Sánchez, Ana; Radwan, Ahmed; Radwan, Islam; Voets, Thomas; Talavera, Karel

doi:10.1016/j.ceca.2013.08.005

Cited by 10 publications

(10 citation statements)

References 42 publications

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“…LPS elicited currents with characteristic signatures of activation of TRPV4, including a reversal potential and a rectification pattern similar to those of currents triggered by the specific agonist GSK1016790A, and inhibition by the TRPV4 antagonist HC067047. We found that TRPV4 responses to LPS were significantly smaller and less prevalent than those to GSK1016790A, which is consistent with the fact that the former compound is a weaker channel agonist 29 . However, the potency of LPS on TRPV4 (11 µg ml −1 ) is within the same range of that previously reported for TRPA1 (~ 3 µg ml −1 ) 8 .…”

Section: Discussionsupporting

confidence: 87%

TRPV4 activation triggers protective responses to bacterial lipopolysaccharides in airway epithelial cells

et al. 2017

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Lipopolysaccharides (LPS), the major components of the wall of gram-negative bacteria, trigger powerful defensive responses in the airways via mechanisms thought to rely solely on the Toll-like receptor 4 (TLR4) immune pathway. Here we show that airway epithelial cells display an increase in intracellular Ca2+ concentration within seconds of LPS application. This response occurs in a TLR4-independent manner, via activation of the transient receptor potential vanilloid 4 cation channel (TRPV4). We found that TRPV4 mediates immediate LPS-induced increases in ciliary beat frequency and the production of bactericidal nitric oxide. Upon LPS challenge TRPV4-deficient mice display exacerbated ventilatory changes and recruitment of polymorphonuclear leukocytes into the airways. We conclude that LPS-induced activation of TRPV4 triggers signaling mechanisms that operate faster and independently from the canonical TLR4 immune pathway, leading to immediate protective responses such as direct antimicrobial action, increase in airway clearance, and the regulation of the inflammatory innate immune reaction.

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Section: Discussionsupporting

confidence: 87%

TRPV4 activation triggers protective responses to bacterial lipopolysaccharides in airway epithelial cells

et al. 2017

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“…2a ). This value is lower than those we have previously found for the correlation between the amplitudes of responses to very low and high concentrations of GSK1016790A [ 39 ]. The average increase in basal [Ca 2+ ] i elicited by 300 μg/ml SiNPs in 16HBE was not significantly different in the absence (0.40 ± 0.04 μM) and in the presence of the specific TRPV4 blocker HC067047 [ 40 ] (0.43 ± 0.05 μM; P = 0.64; Fig.…”

Section: Resultscontrasting

confidence: 71%

Silica nanoparticles inhibit the cation channel TRPV4 in airway epithelial cells

et al. 2017

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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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“…We found that 60 µg/ml LPS induced only very few responses in non-transfected cells (7/110), but stimulated a significantly larger fraction of cells transiently transfected with dTRPA1-A (42/74, P < 10 –4 , Fisher exact test) or dTRPA1-B (14/67, P = 0.007, Fisher exact test) ( Figure 4—figure supplement 4 ). These responses were more variable in amplitude and less frequent than those triggered by AITC, indicating that LPS is a relatively weak agonist of dTRPA1 channels ( Alpizar et al, 2013) . Further evidence for dTRPA1 activation by LPS was obtained in whole-cell patch-clamp experiments, in which application of LPS significantly enhanced both outward and inward currents in dTRPA1-A transfected HEK293T cells, but not control cells ( Figure 4C,D ).…”

Section: Resultsmentioning

confidence: 99%

“… Detecting pathogens and mounting immune responses upon infection is crucial for animal health. However, these responses come at a high metabolic price ( McKean and Lazzaro, 2011 , Kominsky et al, 2010 ), and avoiding pathogens before infection may be advantageous. The bacterial endotoxins lipopolysaccharides (LPS) are important immune system infection cues ( Abbas et al, 2014 ), but it remains unknown whether animals possess sensory mechanisms to detect them prior to infection.…”

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Gustatory-mediated avoidance of bacterial lipopolysaccharides via TRPA1 activation in Drosophila

Soldano

Alpízar

Boonen

et al. 2016

eLife

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Detecting pathogens and mounting immune responses upon infection is crucial for animal health. However, these responses come at a high metabolic price (McKean and Lazzaro, 2011, Kominsky et al., 2010), and avoiding pathogens before infection may be advantageous. The bacterial endotoxins lipopolysaccharides (LPS) are important immune system infection cues (Abbas et al., 2014), but it remains unknown whether animals possess sensory mechanisms to detect them prior to infection. Here we show that Drosophila melanogaster display strong aversive responses to LPS and that gustatory neurons expressing Gr66a bitter receptors mediate avoidance of LPS in feeding and egg laying assays. We found the expression of the chemosensory cation channel dTRPA1 in these cells to be necessary and sufficient for LPS avoidance. Furthermore, LPS stimulates Drosophila neurons in a TRPA1-dependent manner and activates exogenous dTRPA1 channels in human cells. Our findings demonstrate that flies detect bacterial endotoxins via a gustatory pathway through TRPA1 activation as conserved molecular mechanism.DOI: http://dx.doi.org/10.7554/eLife.13133.001

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Lack of correlation between the amplitudes of TRP channel-mediated responses to weak and strong stimuli in intracellular Ca2+ imaging experiments

Cited by 10 publications

References 42 publications

TRPV4 activation triggers protective responses to bacterial lipopolysaccharides in airway epithelial cells

TRPV4 activation triggers protective responses to bacterial lipopolysaccharides in airway epithelial cells

Silica nanoparticles inhibit the cation channel TRPV4 in airway epithelial cells

Gustatory-mediated avoidance of bacterial lipopolysaccharides via TRPA1 activation in Drosophila

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