Ethanol inhibits cold-menthol receptor TRPM8 by modulating its interaction with membrane phosphatidylinositol 4,5-bisphosphate
Ethanol inhibits cold-menthol receptor TRPM8 by modulating its interaction with membrane phosphatidylinositol 4,5-bisphosphate
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DOI：
10.1111/j.1471-4159.2006.04192.x
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发表时间：
2007-01-01
影响因子：
4.7
通讯作者：
Vlachova, Viktorie
中科院分区：
文献类型：
--
作者：
Benedikt, Jan;Teisinger, Jan;Vlachova, Viktorie
乙醇对离子通道瞬时受体电位 (TRP) 家族的两个成员具有相反的作用：它抑制冷薄荷醇受体 TRPM8，而增强热门控和辣椒素门控香草酸受体 TRPV1 的活性。两种热敏阳离子通道均受到膜脂磷脂酰肌醇 4,5-二磷酸 (PIP2) 的严格调节。这种磷脂对 TRPM8 和 TRPV1 的作用在功能上也是相反的：PIP2 对于激活 TRPM8 是必需的，但它会组成性抑制 TRPV1。这种平行引导我们研究 PIP2 在乙醇诱导的大鼠 TRPM8（在 HEK293T 细胞中异源表达）调节中的可能作用。在这项研究中，我们描述了乙醇 (0.1-10%) 对薄荷醇和低温（< 17 摄氏度）产生的全细胞电流的影响。我们发现，细胞内溶液中包含 PIP2 会导致乙醇诱导的薄荷醇诱发反应的抑制作用大大降低。相反，使用抗 PIP2 抗体或 PIP2 清除剂聚 L-赖氨酸进行细胞内透析增强了乙醇诱导的 TRPM8 抑制。与渥曼青霉素预孵育 20 分钟导致 1% 乙醇产生的抑制适度下降，表明乙醇诱导的抑制不是由脂质激酶介导的。这些发现表明乙醇通过削弱 PIP2-TRPM8 通道相互作用来抑制 TRPM8；类似的机制可能有助于乙醇介导的一些其他 PIP2 敏感 TRP 通道的调节。
Ethanol has opposite effects on two members of the transient receptor potential (TRP) family of ion channels: it inhibits the cold-menthol receptor TRPM8, whereas it potentiates the activity of the heat- and capsaicin-gated vanilloid receptor TRPV1. Both thermosensitive cation channels are critically regulated by the membrane lipid, phosphatidylinositol 4,5-bisphosphate (PIP2). The effects of this phospholipid on TRPM8 and TRPV1 are also functionally opposite: PIP2 is necessary for the activation of TRPM8 but it constitutively inhibits TRPV1. This parallel led us to investigate the possible role of PIP2 in the ethanol-induced modulation of rat TRPM8, heterologously expressed in HEK293T cells. In this study, we characterize the effects of ethanol (0.1-10%) on whole-cell currents produced by menthol and by low temperature (< 17 degrees C). We show that the inclusion of PIP2 in the intracellular solution results in a strong reduction in the ethanol-induced inhibition of menthol-evoked responses. Conversely, intracellular dialysis with anti-PIP2 antibody or with the PIP2 scavenger, poly L-lysine, enhanced the ethanol-induced inhibition of TRPM8. A 20 min pre-incubation with wortmannin caused a modest decrease in inhibition produced by 1% ethanol, indicating that the ethanol-induced inhibition is not mediated by lipid kinases. These findings suggest that ethanol inhibits TRPM8 by weakening the PIP2-TRPM8 channel interaction; a similar mechanism may contribute to the ethanol-mediated modulation of some other PIP2-sensitive TRP channels.