Primary alcohols activate human TRPA1 channel in a carbon chain length-dependent manner
Primary alcohols activate human TRPA1 channel in a carbon chain length-dependent manner
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DOI：
10.1007/s00424-011-1069-4
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发表时间：
2012-04-01
影响因子：
4.5
通讯作者：
Tominaga, Makoto
中科院分区：
文献类型：
--
作者：
Komatsu, Tomoko;Uchida, Kunitoshi;Tominaga, Makoto
瞬时受体电位锚蛋白1(TRPA1)是一种钙离子通透性的非选择性阳离子通道，主要在初级伤害性神经元中表达。TRPA1被各种有害刺激激活，包括寒冷的温度，芥子油和肉桂醛等刺激性化合物，以及细胞内碱化。在这里，我们展示了初级酒精，据报道会引起皮肤、眼睛或鼻子刺激，激活人类TRPA1(HTRPA1)。我们测定了1 mM初级酒精诱导表达hTRPA1的HEK293细胞内钙离子的变化。高级醇(正丁醇至正辛醇)表现出与碳链长度成正比的钙增加。在全细胞膜片钳记录中，高级醇(正己醇至正辛醇)激活hTRPA1，且其作用强度随碳链长度的增加而增加。高级醇以内向外方式引起hTRPA1的单通道开放。此外，N端665位的半胱氨酸和C端983位的组氨酸对伯醇激活hTRPA1起重要作用。此外，直链仲醇可增加表达hTRPA1的HEK293细胞内钙离子浓度，并且仲醇和仲醇均表现出与其辛醇/水分配系数高度相关的hTRPA1激活活性。另一方面，小鼠TRPA1对1-己醇或1-辛醇没有表现出强烈的反应，这些醇也没有引起小鼠明显的疼痛。我们得出结论，伯醇和仲醇以碳链长度依赖的方式激活hTRPA1。TRPA1可能是酒精对人体皮肤、眼部和鼻部刺激的感受器。
Transient receptor potential ankyrin 1 (TRPA1) is a calcium-permeable non-selective cation channel that is mainly expressed in primary nociceptive neurons. TRPA1 is activated by a variety of noxious stimuli, including cold temperatures, pungent compounds such as mustard oil and cinnamaldehyde, and intracellular alkalization. Here, we show that primary alcohols, which have been reported to cause skin, eye or nasal irritation, activate human TRPA1 (hTRPA1). We measured intracellular Ca2+ changes in HEK293 cells expressing hTRPA1 induced by 1 mM primary alcohols. Higher alcohols (1-butanol to 1-octanol) showed Ca2+ increases proportional to the carbon chain length. In whole-cell patch-clamp recordings, higher alcohols (1-hexanol to 1-octanol) activated hTRPA1 and the potency increased with the carbon chain length. Higher alcohols evoked single-channel opening of hTRPA1 in an inside-out configuration. In addition, cysteine at 665 in the N terminus and histidine at 983 in the C terminus were important for hTRPA1 activation by primary alcohols. Furthermore, straight-chain secondary alcohols increased intracellular Ca2+ concentrations in HEK293 cells expressing hTRPA1, and both primary and secondary alcohols showed hTRPA1 activation activities that correlated highly with their octanol/water partition coefficients. On the other hand, mouse TRPA1 did not show a strong response to 1-hexanol or 1-octanol, nor did these alcohols evoke significant pain in mice. We conclude that primary and secondary alcohols activate hTRPA1 in a carbon chain length-dependent manner. TRPA1 could be a sensor of alcohols inducing skin, eye and nasal irritation in human.