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Elife. 2019 Jun 11;8. pii: e46084. doi: 10.7554/eLife.46084.

Mouse TRPA1 function and membrane localization are modulated by direct interactions with cholesterol.

Author information

1
Laboratory of Ion Channel Research and TRP Research Platform Leuven (TRPLe), Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
2
VIB Center for Brain & Disease Research, Leuven, Belgium.
3
Center for Microscopy and Molecular Imaging (CMMI), Laboratory of Microscopy, Université Libre de Bruxelles, Gosselies, Belgium.

Abstract

The cation channel TRPA1 transduces a myriad of noxious chemical stimuli into nociceptor electrical excitation and neuropeptide release, leading to pain and neurogenic inflammation. Despite emergent evidence that TRPA1 is regulated by the membrane environment, it remains unknown whether this channel localizes in membrane microdomains or whether it interacts with cholesterol. Using total internal reflection fluorescence microscopy and density gradient centrifugation we found that mouse TRPA1 localizes preferably into cholesterol-rich domains and functional experiments revealed that cholesterol depletion decreases channel sensitivity to chemical agonists. Moreover, we identified two structural motifs in transmembrane segments 2 and 4 involved in mTRPA1-cholesterol interactions that are necessary for normal agonist sensitivity and plasma membrane localization. We discuss the impact of such interactions on TRPA1 gating mechanisms, regulation by the lipid environment, and role of this channel in sensory membrane microdomains, all of which helps to understand the puzzling pharmacology and pathophysiology of this channel.

KEYWORDS:

CRAC motif; TRPA1; biochemistry; chemical biology; chemosensation; cholesterol; lipid raft; mouse; neuroscience; sensory neuron

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