Deficiency of Inositol Monophosphatase Activity Decreases Phosphoinositide Lipids and Enhances TRPV1 Function In Vivo.
Deficiency of Inositol Monophosphatase Activity Decreases Phosphoinositide Lipids and Enhances TRPV1 Function In Vivo.
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DOI：
10.1523/jneurosci.0803-20.2020
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发表时间：
2021-01-20
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影响因子：
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通讯作者：
Cordero-Morales JF
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文献类型：
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作者：
Caires R;Bell B;Lee J;Romero LO;Vásquez V;Cordero-Morales JF
炎症介质引起的膜重构影响感觉离子通道的功能。辣椒素和热激活的瞬时受体电位香草酸1（TRPV 1）通道有助于神经源性炎症和疼痛超敏反应，部分原因是其调节磷酸肌醇脂质含量的磷脂酶C偶联受体下游的增强作用。炎症介质引起的膜重构影响感觉离子通道的功能。辣椒素和热激活的瞬时受体电位香草酸1（TRPV 1）通道有助于神经源性炎症和疼痛超敏反应，部分原因是其调节磷酸肌醇脂质含量的磷脂酶C偶联受体下游的增强作用。在这里，我们确定了磷酸肌醇脂质对TRPV 1功能的影响，结合遗传解剖，饮食补充，行为，生化和功能分析秀丽隐杆线虫。由于辣椒素在哺乳动物中引起热和疼痛感，转基因TRPV 1蠕虫对辣椒素表现出厌恶反应。具有低水平磷酸肌醇脂质的TRPV 1蠕虫显示对辣椒素的反应增强，而磷酸肌醇脂质补充剂降低TRPV 1介导的反应。携带TRPV 1构建体的蠕虫缺乏远端C-末端结构域，其特征在于对辣椒素的反应增强，与磷酸肌醇脂质含量无关。我们的研究结果表明，TRPV 1活性增强时，磷脂酰肌醇脂质含量减少，C-末端结构域是关键，以确定激动剂在体内的反应。
Membrane remodeling by inflammatory mediators influences the function of sensory ion channels. The capsaicin- and heat-activated transient receptor potential vanilloid 1 (TRPV1) channel contributes to neurogenic inflammation and pain hypersensitivity, in part because of its potentiation downstream of phospholipase C-coupled receptors that regulate phosphoinositide lipid content. Membrane remodeling by inflammatory mediators influences the function of sensory ion channels. The capsaicin- and heat-activated transient receptor potential vanilloid 1 (TRPV1) channel contributes to neurogenic inflammation and pain hypersensitivity, in part because of its potentiation downstream of phospholipase C-coupled receptors that regulate phosphoinositide lipid content. Here, we determined the effect of phosphoinositide lipids on TRPV1 function by combining genetic dissection, diet supplementation, and behavioral, biochemical, and functional analyses in Caenorhabditis elegans. As capsaicin elicits heat and pain sensations in mammals, transgenic TRPV1 worms exhibit an aversive response to capsaicin. TRPV1 worms with low levels of phosphoinositide lipids display an enhanced response to capsaicin, whereas phosphoinositide lipid supplementation reduces TRPV1-mediated responses. A worm carrying a TRPV1 construct lacking the distal C-terminal domain features an enhanced response to capsaicin, independent of the phosphoinositide lipid content. Our results demonstrate that TRPV1 activity is enhanced when the phosphoinositide lipid content is reduced, and the C-terminal domain is key to determining agonist response in vivo.