TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase
TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase
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DOI：
10.1523/jneurosci.4643-06.2007
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发表时间：
2007-02-28
影响因子：
5.3
通讯作者：
Oh, Uhtaek
中科院分区：
文献类型：
--
作者：
Shim, Won-Sik;Tak, Min-Ho;Oh, Uhtaek
组胺引起瘙痒，是一种主要的皮肤病。已知组胺刺激感觉神经元的子集，主要是C纤维。虽然组胺是致敏的，但其兴奋感觉神经元的信号通路尚未确定。由于脂氧合酶（LO）的代谢产物激活感觉神经元中的瞬时受体电位香草酸受体1（TRPV 1），我们假设组胺通过磷脂酶A（2）（PLA（2））和LO刺激激活TRPV 1来兴奋感觉神经元。在培养的感觉神经元中，组胺诱发的内向电流被TRPV 1阻断剂辣椒平（capsazepine）降低。此外，组胺引起内向电流时，组胺受体亚型1（H1 R）和TRPV 1异源表达，但不是当H1 R或TRPV 1单独表达。此外，组胺引起野生型小鼠感觉神经元中的Ca 2+内流，但在TRPV 1（-/-）小鼠中不引起。此外，组胺引起的12-hydroxyyeicosatetraenoic酸，L0的代谢产物，在培养的感觉神经元的生产增加了2.5倍。当将组胺皮下注射到小鼠颈部时，会引起抓挠发作，而预先用辣椒平（一种TRPV 1阻断剂）和PLA（2）、L0和H1 R抑制剂可大大减轻这种情况。此外，与野生型相比，缺乏TRPV 1的小鼠显着减少组胺诱导的抓挠。总之，这些结果表明TRPV 1在通过PLA（2）/LO途径介导组胺的致炎作用中起关键作用。
Histamine provokes itching and is a major skin disease complaint. Histamine is known to excite a subset of sensory neurons, predominantly C-fibers. Although histamine is pruritogenic, its signaling pathways that excite sensory neurons have not been identified. Because the metabolic products of lipoxygenases (LOs) activate transient receptor potential vanilloid receptor-1 (TRPV1) in sensory neurons, we hypothesized that histamine excites sensory neurons by activating TRPV1 via phospholipase A(2) (PLA(2)) and L0 stimulation. In cultured sensory neurons, histamine evoked inward currents that were reduced by capsazepine, a TRPV1 blocker. Moreover, histamine provoked inward currents when histamine receptor subtype 1 ( H1R) and TRPV1 were expressed heterologously, but not when H1R or TRPV1 was expressed alone. In addition, histamine caused Ca2+ influxes in sensory neurons in wild-type mice but not in TRPV1(-/-) mice. Furthermore, histamine caused a 2.5-fold increase in the production of 12-hydroxyeicosatetraenoic acid, a metabolite of L0, in cultured sensory neurons. When injected subcutaneously into the necks of mice, histamine caused bouts of scratching, which were greatly reduced by pretreatment with capsazepine, a TRPV1 blocker, and by inhibitors of PLA(2), L0, and H1R. Furthermore, mice lacking TRPV1 markedly reduced histamine-induced scratching compared with wild type. Together, these results indicate that TRPV1 plays a key role in mediating the pruritogenic action of histamine via the PLA(2)/LO pathway.