TRP Channels as Sensors of Chemically-Induced Changes in Cell Membrane Mechanical Properties

Startek, Justyna B.; Boonen, Brett; Talavera, Karel; Meseguer, Víctor

doi:10.3390/ijms20020371

Cited by 59 publications

(48 citation statements)

References 189 publications

(241 reference statements)

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“…Another interesting aspect on TRPA1 mechanosensation is that the effect of non-electrophilic TRPA1 ligands may be indirect by changing the lipid tension stress on TRPA1 within the cell membrane (17). For example, the ability of primary and secondary alcohols as well as different alkyl-substituted phenol derivatives including carvacrol to activate hTRPA1 increased with increasing lipophilicity (17). Our observation that carvacrol induced conformational changes of purified hTRPA1 in a bilayer-free environment indicates, however, a direct interaction with TRPA1 (9).…”

Section: Discussionmentioning

confidence: 99%

Human TRPA1 is an inherently mechanosensitive bilayer-gated ion channel

Moparthi

Zygmunt

2020

Preprint

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The Transient Receptor Potential Ankyrin 1 (TRPA1) channel is an intrinsic chemo-and thermo-sensitive ion channel with distinct sensory signaling properties. Although a role of TRPA1 in mammalian mechanosensory transduction in vivo seems likely, it remains to be shown that TRPA1 has the inherent capability to respond to mechanical stimuli. Here we have used the patch-clamp technique to study the response of human purified TRPA1 (hTRPA1), reconstituted into artificial lipid bilayers, to changes in bilayer pressure. We report that hTRPA1 responded with increased single-channel open probability (Po) within the applied pressure interval of 7.5 to 60 mmHg with a half maximum Po (P50) value of 38.0 ± 2.3 mmHg. The Po value reached a maximum close to 1 (0.87 ± 0.02) at 60 mmHg. Within the same pressure interval, hTRPA1 without its N-terminal ankyrin repeat domain (Δ1-688 hTRPA1) responded fully opened (0.99 ± 0.01) at 60 mmHg and with a P50 value of 39.0 ± 1.1 mmHg. The pressure-evoked responses of hTRPA1 and Δ1-688 hTRPA1 at 45 mmHg were inhibited by the TRPA1 antagonist HC030031, and the activity of purified hTRPA1 at 45 mmHg was abolished by the thiol reducing agent tris(2-carboxyethyl)phosphine (TCEP). In conclusion, hTRPA1 is an inherent mechanosensitive ion channel gated by force-from-lipids. The hTRPA1 mechanosensitivity is dependent on the redox environment, and it is suggested that oxidative stress shifts hTRPA1 into a protein conformation sensitive to mechanical stimuli.

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Section: Discussionmentioning

confidence: 99%

Human TRPA1 is an inherently mechanosensitive bilayer-gated ion channel

Moparthi

Zygmunt

2020

Preprint

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“…The authors identified by in silico investigation cholesterol recognition amino acid consensus motifs in the TM2 and TM4 segments, which had a role in the inhibition of chemical activation of mouse TRPA1 by cholesterol depletors [ 34 ]. Cholesterol might influence TRP channel function by direct interaction with ion channels [ 34 , 35 , 36 ]. Sphingomyelinase hydrolyzes SM to phosphocholine and ceramide [ 37 , 38 ].…”

Section: Introductionmentioning

confidence: 99%

Resolvin D1 and D2 Inhibit Transient Receptor Potential Vanilloid 1 and Ankyrin 1 Ion Channel Activation on Sensory Neurons via Lipid Raft Modification

Payrits

Horváth

Bíró-Sütő

et al. 2020

IJMS

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Transient Receptor Potential Vanilloid 1 and Ankyrin 1 (TRPV1, TRPA1) cation channels are expressed in nociceptive primary sensory neurons and regulate nociceptor and inflammatory functions. Resolvins are endogenous lipid mediators. Resolvin D1 (RvD1) is described as a selective inhibitor of TRPA1-related postoperative and inflammatory pain in mice acting on the G protein-coupled receptor DRV1/GPR32. Resolvin D2 (RvD2) is a very potent TRPV1 and TRPA1 inhibitor in DRG neurons, and decreases inflammatory pain in mice acting on the GPR18 receptor, via TRPV1/TRPA1-independent mechanisms. We provided evidence that resolvins inhibited neuropeptide release from the stimulated sensory nerve terminals by TRPV1 and TRPA1 activators capsaicin (CAPS) and allyl-isothiocyanate (AITC), respectively. We showed that RvD1 and RvD2 in nanomolar concentrations significantly decreased TRPV1 and TRPA1 activation on sensory neurons by fluorescent calcium imaging and inhibited the CAPS- and AITC-evoked 45Ca-uptake on TRPV1- and TRPA1-expressing CHO cells. Since CHO cells are unlikely to express resolvin receptors, resolvins are suggested to inhibit channel opening through surrounding lipid raft disruption. Here, we proved the ability of resolvins to alter the membrane polarity related to cholesterol composition by fluorescence spectroscopy. It is concluded that targeting lipid raft integrity can open novel peripheral analgesic opportunities by decreasing the activation of nociceptors.

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“…The molecular mechanism underlying TRPV4 activation by LPS remains to be fully clarified. However, because of the widely reported mechanosensitivity of this channel (34-36), we hypothesize that it could be similar as that operating in TRPA1, i.e., via the detection of LPS-induced mechanical perturbations in the plasma membrane (27,(37)(38)(39).…”

Section: Discussionmentioning

confidence: 95%

TRPV4 Mediates Acute Bladder Responses to Bacterial Lipopolysaccharides

et al. 2020

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Urinary tract infections (UTI) affect a large proportion of the population, causing among other symptoms, more frequent and urgent micturition. Previous studies reported that the gram-negative bacterial wall component lipopolysaccharides (LPS) trigger acute epithelial and bladder voiding responses, but the underlying mechanisms remain unknown. The cation channel TRPV4 is implicated in the regulation of the bladder voiding. Since TRPV4 is activated by LPS in airway epithelial cells, we sought to determine whether this channel plays a role in LPS-induced responses in urothelial cells (UCs). We found that human-derived UCs display a fast increase in intracellular Ca 2+ concentration upon acute application of Escherichia coli LPS. Such responses were detected also in freshly isolated mouse UCs, and found to be dependent on TRPV4, but not to require the canonical TLR4 signaling pathway of LPS detection. Confocal microscopy experiments revealed that TRPV4 is dispensable for LPS-induced nuclear translocation of NF-κB in mouse UCs. On the other hand, quantitative RT PCR determinations showed an enhanced LPS-induced production of proinflammatory cytokines in TRPV4-deficient UCs. Cystometry experiments in anesthetized wild type mice revealed that acute intravesical instillation of LPS rapidly increases voiding frequency. This effect was not observed in TRPV4-deficient animals, but was largely preserved in Tlr4 KO and Trpa1 KO mice. Our results suggest that activation of TRPV4 by LPS in UCs regulates the proinflammatory response and contributes to LPS-induced increase in voiding frequency. These findings further support the concept that TRP channels are sensors of LPS, mediating fast innate immunity mechanisms against gram-negative bacteria.

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TRP Channels as Sensors of Chemically-Induced Changes in Cell Membrane Mechanical Properties

Cited by 59 publications

References 189 publications

Human TRPA1 is an inherently mechanosensitive bilayer-gated ion channel

Human TRPA1 is an inherently mechanosensitive bilayer-gated ion channel

Resolvin D1 and D2 Inhibit Transient Receptor Potential Vanilloid 1 and Ankyrin 1 Ion Channel Activation on Sensory Neurons via Lipid Raft Modification

TRPV4 Mediates Acute Bladder Responses to Bacterial Lipopolysaccharides

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