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The Agonist Action of Alkylphenols on TRPA1 Relates to Their Effects on Membrane Lipid Order: Implications for TRPA1-Mediated Chemosensation

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The Transient Receptor Potential Ankyrin 1 cation channel (TRPA1) is a broadly-tunedchemosensor expressed in nociceptive neurons. Multiple TRPA1 agonists are chemically unrelatednon-electrophilic compounds, for which the mechanisms of channel activation remain unknown.Here, we assess the hypothesis that such chemicals activate TRPA1 by inducing mechanical perturbations in the plasma membrane. We characterized the activation of mouse TRPA1 by non-electrophilicalkylphenols (APs) of different carbon chain lengths in the para position of the aromatic ring. Havingdiscarded oxidative stress and the action of electrophilic mediators as activation mechanisms, wedetermined whether APs induce mechanical perturbations in the plasma membrane using dyeswhose fluorescence properties change upon alteration of the lipid environment. APs activatedTRPA1, with potency increasing with their lipophilicity. APs increased the generalized polarization ofLaurdan fluorescence and the anisotropy of the fluorescence of 1,6-diphenyl-1,3,5-hexatriene (DPH),also according to their lipophilicity. Thus, the potency of APs for TRPA1 activation is an increasingfunction of their ability to induce lipid order and membrane rigidity. These results support thehypothesis that TRPA1 senses non-electrophilic compounds by detecting the mechanical alterationsthey produce in the plasma membrane. This may explain how structurally unrelated non-reactivecompounds induce TRPA1 activation and support the role of TRPA1 as an unspecific sensor ofpotentially noxious compounds.
Tijdschrift: International Journal of Molecular Sciences
ISSN: 1661-6596
Issue: 7
Volume: 22
Aantal pagina's: 21
Jaar van publicatie:2021
Trefwoorden:Biochemie & -fysica en Moleculaire biologie, Multidisciplinaire scheikunde