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Title: | Mouse TRPA1 function and membrane localization are modulated by direct interactions with cholesterol | Authors: | Startek, Justyna B Boonen, Brett López-Requena, Alejandro Talavera, Ariel AGUIAR ALPIZAR, Yeranddy Ghosh, Debapriya Van Ranst, Nele Nilius, Bernd Voets, Thomas Talavera, Karel |
Issue Date: | 2019 | Publisher: | ELIFE SCIENCES PUBLICATIONS LTD | Source: | eLife, 8 (Art N° e46084) | 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: | Receptor Potential A1;Trigeminal Sensory Neurons;Peripheral Nervous-System;Trpm8 Channel;Ion Channels;Cold Hypersensitivity;Heat Activation;Lipid Rafts;Expression;Mechanism | Document URI: | http://hdl.handle.net/1942/30199 | ISSN: | 2050-084X | e-ISSN: | 2050-084X | DOI: | 10.7554/eLife.46084 | ISI #: | 000472714200001 | Rights: | Copyright Startek et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. | Category: | A1 | Type: | Journal Contribution |
Appears in Collections: | Research publications |
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elife-46084-v2.pdf | Published version | 5.47 MB | Adobe PDF | View/Open |
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