Laboratory of Ion Channel Research and TRP Research Platform Leuven (TRPLe), Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
VIB Center for Brain & Disease Research, Leuven, Belgium.
Elife. 2019 Jun 11;8:e46084. doi: 10.7554/eLife.46084.
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.
阳离子通道 TRPA1 将多种有害化学刺激转化为伤害感受器的电兴奋和神经肽释放，导致疼痛和神经源性炎症。尽管有新的证据表明 TRPA1 受膜环境调节，但尚不清楚该通道是否定位于膜微区，或者是否与胆固醇相互作用。使用全内反射荧光显微镜和密度梯度离心，我们发现小鼠 TRPA1 优先定位于富含胆固醇的区域，功能实验表明胆固醇耗竭会降低通道对化学激动剂的敏感性。此外，我们鉴定出跨膜片段 2 和 4 中的两个结构基序参与 mTRPA1-胆固醇相互作用，这对于正常的激动剂敏感性和质膜定位是必需的。我们讨论了这种相互作用对 TRPA1 门控机制、脂质环境调节以及该通道在感觉膜微区中的作用的影响，所有这些都有助于理解该通道令人困惑的药理学和病理生理学。
