Activation of TRPV1 by the satiety factor oleoylethanolamide
Activation of TRPV1 by the satiety factor oleoylethanolamide
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DOI：
10.1074/jbc.m305051200
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发表时间：
2003-08-15
影响因子：
4.8
通讯作者：
Ahern, GP
中科院分区：
文献类型：
--
作者：
Ahern, GP
脂肪酸油酰乙醇胺(OEA)是一种刺激周围迷走神经的饱腹感因子，但其发生机制和分子靶点尚不清楚。本研究探讨了OEA对辣椒素受体(TRPV1)的调节作用。在对照条件下，OEA本身并不激活非洲爪哇卵母细胞中表达的TRPV1，但对激动剂诱发的反应产生了不同的调制。OEA可增强质子门控的TRPV1电流，抑制ANANDAME诱发的电流，但对辣椒素诱发的反应无影响。在蛋白激酶C(PKC)刺激后，OEA单独直接激活TRPV1通道，其EC50在室温下接近2um。这一效应是由于TRPV1的直接磷酸化，因为没有观察到对OEA的反应，突变的通道缺乏关键的PKC磷酸化位点S502A/S800A。在感觉神经元中，OEA诱导的钙升高对辣椒素敏感的细胞是选择性的，被TRPV1阻断剂Capsazepine抑制，并以PKC依赖的方式发生。此外，在PKC刺激后，OEA激活了无细胞斑块中的TRPV1通道，这表明了一种直接的作用模式。因此，TRPV1是OEA的潜在靶点，并可能参与OEA对感觉神经的兴奋作用。
The fatty acid oleoylethanolamide (OEA) is a satiety factor that excites peripheral vagal sensory nerves, but the mechanism by which this occurs and the molecular targets of OEA are unclear. In this study the ability of OEA to modulate the capsaicin receptor (TRPV1) was explored. OEA alone did not activate TRPV1 expressed in Xenopus oocytes under control conditions, but produced a differential modulation of agonist-evoked responses. OEA enhanced proton-gated TRPV1 currents, inhibited anandamide-evoked currents and had no effect on capsaicin-evoked responses. Following stimulation of protein kinase C (PKC), OEA alone directly activated TRPV1 channel with an EC50 of similar to2 muM at room temperature. This effect was due to direct phosphorylation of TRPV1 because no responses to OEA were observed with mutant channels lacking critical PKC phosphorylation sites, S502A/S800A. In sensory neurons, OEA-induced Ca2+ rises that were selective for capsaicin-sensitive cells, inhibited by the TRPV1 blocker, capsazepine, and occurred in a PKC-dependent manner. Further, after PKC stimulation, OEA activated TRPV1 channels in cell-free patches suggesting a direct mode of action. Thus, TRPV1 represents a potential target for OEA and may contribute to the excitatory action of OEA on sensory nerves.