Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain
Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain
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DOI：
10.1172/jci30951
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发表时间：
2007-07-01
影响因子：
15.9
通讯作者：
Noguchi, Koichi
中科院分区：
文献类型：
--
作者：
Dai, Yi;Wang, Shenglan;Noguchi, Koichi
促炎剂胰蛋白酶和肥大细胞胰蛋白酶裂解并激活PAR2， PAR2在感觉神经上表达，引起神经源性炎症。瞬时受体电位A1 （TRPA1）是疼痛通路初级感觉神经上的兴奋性离子通道。在这里，我们发现背根神经节（DRG）神经元中PAR2和TRPA1的功能相互作用可能有助于炎症性疼痛的感觉。在大鼠DRG神经元中发现TRPA1与PAR2频繁共定位。在TRPA1转染的HEK293细胞和DRG神经元中，PAR2激活增加了其激动剂引起的TRPA1电流。磷脂酶C （PLC）抑制剂或磷脂酰肌醇-4,5-二磷酸（PIP2）的应用抑制了这种增强。通过抗体隔离或plc介导的水解降低质膜PIP2水平在细胞水平上模拟了PAR2活化的增强作用。因此，TRPA1敏感性的增加可能是由于PLC的激活，从而释放了质膜PIP2对TRPA1的抑制。据我们所知，这些结果首次确定了TRPA1的致敏机制，以及组织炎症反应中释放的胰蛋白酶或胰蛋白酶可能通过TRPA1激活触发疼痛感觉的新机制。
Proinflammatory agents trypsin and mast cell tryptase cleave and activate PAR2, which is expressed on sensory nerves to cause neurogenic inflammation. Transient receptor potential A1 (TRPA1) is an excitatory ion channel on primary sensory nerves of pain pathway. Here, we show that a functional interaction of PAR2 and TRPA1 in dorsal root ganglion (DRG) neurons could contribute to the sensation of inflammatory pain. Frequent colocalization of TRPA1 with PAR2 was found in rat DRG neurons. PAR2 activation increased the TRPA1 currents evoked by its agonists in HEK293 cells transfected with TRPA1, as well as DRG neurons. Application of phospholipase C (PLC) inhibitors or phosphatidylinositol-4,5-bisphosphate (PIP2) suppressed this potentiation. Decrease of plasma membrane PIP2 levels through antibody sequestration or PLC-mediated hydrolysis mimicked the potentiating effects of PAR2 activation at the cellular level. Thus, the increased TRPA1 sensitivity may have been due to activation of PLC, which releases the inhibition of TRPA1 from plasma membrane PIP2. These results identify for the first time to our knowledge a sensitization mechanism of TRPA1 and a novel mechanism through which trypsin or tryptase released in response to tissue inflammation might trigger the sensation of pain by TRPA1 activation.