Agonist-induced sensitisation of the irritant receptor ion channel TRPA1
Agonist-induced sensitisation of the irritant receptor ion channel TRPA1
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DOI：
10.1113/jp272237
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发表时间：
2016-11-15
影响因子：
5.5
通讯作者：
McNaughton, Peter A.
中科院分区：
文献类型：
--
作者：
Meents, Jannis E.;Fischer, Michael J. M.;McNaughton, Peter A.
TRPA 1离子通道在伤害感受（疼痛敏感）神经元中表达，并对各种化学刺激物（如烟雾中的丙烯醛或芥末中的异硫氰酸酯）作出反应。在这里，我们表明，在细胞外钙的情况下，通过TRPA 1的电流逐渐增加（敏感性），在长期应用激动剂。激动剂的激活是必不可少的，因为TRPA 1通过膜去极化的激活不会引起致敏。致敏作用与激动剂的作用部位无关，因为共价和非共价激动剂同样有效，并且在去除激动剂后持续时间长。突变的N-末端半胱氨酸，共价激动剂的目标，不影响敏化的非共价激动剂香芹酚，激活结合到不同的网站。致敏作用不受阻断离子通道运输或阻断涉及ATP、蛋白激酶A或脂筏形成的信号传导途径的药物的影响，并且不需要通过通道的离子通量。TRPA 1激活的电压依赖性的检查表明，敏化伴随着TRPA 1的电压依赖性向更负的膜电位的缓慢发展的转变，因此是TRPA 1通道固有的。致敏作用可能在加剧由TRPA 1的长期激活引起的疼痛中起作用。
The TRPA1 ion channel is expressed in nociceptive (pain-sensitive) neurons and responds to a wide variety of chemical irritants, such as acrolein in smoke or isothiocyanates in mustard. Here we show that in the absence of extracellular calcium the current passing through TRPA1 gradually increases (sensitises) during prolonged application of agonists. Activation by an agonist is essential, because activation of TRPA1 by membrane depolarisation did not cause sensitisation. Sensitisation is independent of the site of action of the agonist, because covalent and non-covalent agonists were equally effective, and is long lasting following agonist removal. Mutating N-terminal cysteines, the target of covalent agonists, did not affect sensitisation by the non-covalent agonist carvacrol, which activates by binding to a different site. Sensitisation is unaffected by agents blocking ion channel trafficking or by block of signalling pathways involving ATP, protein kinase A or the formation of lipid rafts, and does not require ion flux through the channel. Examination of the voltage dependence of TRPA1 activation shows that sensitisation is accompanied by a slowly developing shift in the voltage dependence of TRPA1 towards more negative membrane potentials, and is therefore intrinsic to the TRPA1 channel. Sensitisation may play a role in exacerbating the pain caused by prolonged activation of TRPA1.