Bimodal effects of cinnamaldehyde and camphor on mouse TRPA1
Bimodal effects of cinnamaldehyde and camphor on mouse TRPA1
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DOI：
10.1007/s00424-012-1204-x
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发表时间：
2013-06-01
影响因子：
4.5
通讯作者：
Talavera, Karel
中科院分区：
文献类型：
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作者：
Alpizar, Yeranddy A.;Gees, Maarten;Talavera, Karel
TRPA 1是一种非选择性阳离子通道，可被多种有毒化学物质激活。有趣的是，几种TRPA 1调节剂诱导双峰效应，在微摩尔浓度下激活通道并在更高浓度下抑制它。在这里，我们报告的双峰行动肉桂醛（CA）和樟脑，这是迄今为止报道的激动剂和拮抗剂的TRPA 1，分别。全细胞膜片钳实验TRPA 1表达CHO细胞显示，如前所述，细胞外应用100 μ M CA强烈刺激TRPA 1电流。然而，随后应用3 mM CA诱导快速和可逆的电流抑制。在基础条件下应用3 mM CA诱导了相当小的电流增加，随后是电流抑制和洗脱后电流振幅的急剧反弹。这些观察结果使人想起具有双峰效应的TRPA 1调节剂的作用，例如，薄荷醇和尼古丁。与以前的报道一致，细胞外应用1 mM樟脑诱导基础TRPA 1电流减少。然而，电流振幅在洗脱时显示出显著的过冲。另一方面，应用100 μ M樟脑诱导在-75 mV下测量的基础电流幅度增加3倍。CA和樟脑对TRPA 1的双峰效应还观察到在完整的TRPA 1表达CHO细胞和小鼠背根神经节神经元的原代培养物中细胞内Ca 2+的显微荧光测量。这些发现对于理解这些化合物的复杂感觉特性以及用于研究TRPA 1的病理生理相关性时的实用性至关重要。
TRPA1 is a nonselective cation channel activated by a wide variety of noxious chemicals. Intriguingly, several TRPA1 modulators induce a bimodal effect, activating the channel at micromolar concentrations and inhibiting it at higher concentrations. Here we report the bimodal action of cinnamaldehyde (CA) and camphor, which are thus far reported as agonist and antagonist of TRPA1, respectively. Whole-cell patch-clamp experiments in TRPA1-expressing CHO cells revealed that, as previously reported, extracellular application of 100 mu M CA strongly stimulates TRPA1 currents. However, subsequent application of 3 mM CA induced fast and reversible current inhibition. Application of 3 mM CA in basal conditions induced a rather small current increase, followed by current inhibition and a dramatic rebound of current amplitude upon washout. These observations are reminiscent of the effects of TRPA1 modulators having bimodal effects, e.g., menthol and nicotine. In line with previous reports, extracellular application of 1 mM camphor induced a decrease of basal TRPA1 currents. However, the current amplitude showed a significant overshoot upon washout. On the other hand, application of 100 mu M camphor induced a 3-fold increase of the basal current amplitude measured at -75 mV. The bimodal effects of CA and camphor on TRPA1 were also observed in microfluorimetric measurements of intracellular Ca2+ in intact TRPA1-expressing CHO cells and in primary cultures of mouse dorsal root ganglion neurons. These findings are essential for the understanding of the complex sensory properties of these compounds, as well as their utility when used to study the pathophysiological relevance of TRPA1.