The roles of iPLA2, TRPM8 and TRPA1 in chemically induced cold hypersensitivity.
The roles of iPLA2, TRPM8 and TRPA1 in chemically induced cold hypersensitivity.
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DOI：
10.1186/1744-8069-6-4
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发表时间：
2010-01-21
期刊：
影响因子：
3.3
通讯作者：
Bevan S
中科院分区：
文献类型：
--
作者：
Gentry C;Stoakley N;Andersson DA;Bevan S
清凉剂薄荷醇和icilin作为TRPM 8和TRPA 1的激动剂。在体外，由icilin和冷而不是薄荷醇激活TRPM 8依赖于磷脂酶A2的亚型iPLA 2的活性。由PLA 2活性产生的溶血磷脂（例如LPC）也可以激活TRPM 8。TRPA 1在体外作为主要冷传感器的作用是有争议的，尽管有证据表明TRPA 1在对有害冷刺激的行为反应中起作用。在这项研究中，我们研究了TRPM 8和TRPA 1的作用以及iPLA 2对幼稚动物和局部施用薄荷醇，icilin和LPC后的有害冷敏感性的影响。在缺乏TRPM 8（Trpm 8-/-）或TRPA 1（Trpa 1-/-）的小鼠中研究了通道在冷敏感性中的作用。足底内施用icilin引起对10°C刺激的敏感性的剂量依赖性增加，其被BEL的iPLA 2抑制所抑制。与此相反，BEL处理不抑制由足底薄荷醇和LPC引起的冷过敏。BEL对TRPV 1激动剂辣椒素和P2 X3激动剂α，β-亚甲基ATP诱导的基础冷敏感性和机械超敏反应没有影响。Trpm 8-/-和Trpa 1-/-小鼠从10°C刺激中缩回爪子的时间比野生型同窝出生的小鼠长。由icilin或LPC诱导的冷过敏在Trpm 8-/-小鼠中不存在，但在Trpa 1-/-小鼠中保留。相反，薄荷醇引起的冷超敏反应存在于Trpm 8-/-小鼠中，但在Trpa 1-/-小鼠中消失。iPLA 2抑制阻断了icilin给药后冷超敏反应的发展，但未能影响薄荷醇诱导的超敏反应，这一发现与我们早期的体外数据一致，这些数据显示了iPLA 2抑制对这些药物的激动剂活性的不同影响。LPC诱导冷超敏反应的能力支持iPLA 2在体内调节TRPM 8活性中的作用。对转基因小鼠的研究表明，icilin和LPC的作用是由TRPM 8介导的，而不是TRPA 1。与此相反，薄荷醇诱导的冷过敏依赖于TRPA 1的表达，而不是TRPM 8。
The cooling agents menthol and icilin act as agonists at TRPM8 and TRPA1. In vitro, activation of TRPM8 by icilin and cold, but not menthol, is dependent on the activity of a sub-type of phospholipase A2, iPLA2. Lysophospholipids (e.g. LPC) produced by PLA2 activity can also activate TRPM8. The role of TRPA1 as a primary cold sensor in vitro is controversial, although there is evidence that TRPA1 plays a role in behavioural responses to noxious cold stimuli. In this study, we have investigated the roles of TRPM8 and TRPA1 and the influence of iPLA2 on noxious cold sensitivities in naïve animals and after local administration of menthol, icilin and LPC. The roles of the channels in cold sensitivity were investigated in mice lacking either TRPM8 (Trpm8-/-) or TRPA1 (Trpa1-/-). Intraplantar administration of icilin evoked a dose-dependent increase in sensitivity to a 10°C stimulus that was inhibited by iPLA2 inhibition with BEL. In contrast the cold hypersensitivities elicited by intraplantar menthol and LPC were not inhibited by BEL treatment. BEL had no effect on basal cold sensitivity and mechanical hypersensitivities induced by the TRPV1 agonist, capsaicin, and the P2X3 agonist α,β-methylene ATP. Both Trpm8-/- and Trpa1-/- mice showed longer latencies for paw withdrawal from a 10°C stimulus than wild-type littermates. Cold hypersensitivities induced by either icilin or LPC were absent in Trpm8-/- mice but were retained in Trpa1-/- mice. In contrast, cold hypersensitivity evoked by menthol was present in Trpm8-/- mice but was lost in Trpa1-/- mice. The findings that iPLA2 inhibition blocked the development of cold hypersensitivity after administration of icilin but failed to affect menthol-induced hypersensitivity agree well with our earlier in vitro data showing a differential effect of iPLA2 inhibition on the agonist activities of these agents. The ability of LPC to induce cold hypersensitivity supports a role for iPLA2 in modulating TRPM8 activity in vivo. Studies on genetically modified mice demonstrated that the effects of icilin and LPC were mediated by TRPM8 and not TRPA1. In contrast, menthol-induced cold hypersensitivity was dependent on expression of TRPA1 and not TRPM8.
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影响因子：
3.3
作者：
Petrus M;Peier AM;Bandell M;Hwang SW;Huynh T;Olney N;Jegla T;Patapoutian A
通讯作者：
Patapoutian A
DOI：
10.1073/pnas.0812675106
发表时间：
2009-05-19
影响因子：
11.1
作者：
Andersson, David A.;Gentry, Clive;Bevan, Stuart
通讯作者：
Bevan, Stuart
影响因子：
16.2
作者：
Kwan, KY;Allchorne, AJ;Corey, DP
通讯作者：
Corey, DP
影响因子：
4
作者：
Munns, Clare;AlQatari, Mona;Koltzenburg, Martin
通讯作者：
Koltzenburg, Martin
影响因子：
3.3
作者：
Klionsky, Lana;Tamir, Rami;Gavva, Narender R.
通讯作者：
Gavva, Narender R.