Transient Receptor Potential Vanilloid 4 Ion Channel Functions as a Pruriceptor in Epidermal Keratinocytes to Evoke Histaminergic Itch.
Transient Receptor Potential Vanilloid 4 Ion Channel Functions as a Pruriceptor in Epidermal Keratinocytes to Evoke Histaminergic Itch.
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DOI：
10.1074/jbc.m116.716464
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发表时间：
2016-05-06
期刊：
影响因子：
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通讯作者：
Liedtke WB
中科院分区：
文献类型：
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作者：
Chen Y;Fang Q;Wang Z;Zhang JY;MacLeod AS;Hall RP;Liedtke WB
TRPV4 离子通道在表皮角质形成细胞和支配感觉神经元中发挥作用；然而，任一细胞中的通道对神经感觉功能的贡献仍有待阐明。我们最近报道 TRPV4 是角质形成细胞机制的关键组成部分，它对紫外线 B (UVB) 做出反应，并在过量 UVB 暴露后将角质形成细胞转化为疼痛产生细胞。角质形成细胞的一个关键机制是内皮素-1 的表达和分泌增加，内皮素-1 也是一种已知的瘙痒剂。在这里，我们解决了皮肤角质形成细胞中的 TRPV4 是否作为非神经细胞中“前线”信号传导的一种特殊形式在瘙痒中发挥作用的问题。我们的结果支持这一新概念，该概念基于 Trpv4 角质形成细胞特异性和诱导型敲除小鼠中对组胺能（组胺、化合物 48/80、内皮素-1）而不是非组胺能（氯喹）瘙痒原的抓挠行为减弱。我们证明角质形成细胞依赖 TRPV4 进行钙内流以响应组胺能瘙痒原。角质形成细胞中的 TRPV4 激活会引起丝裂原激活蛋白激酶 (ERK) 磷酸化，产生组胺能瘙痒原。这一发现是相关的，因为我们观察到局部应用 TRPV4 和 MEK（ERK 上游激酶）选择性抑制剂具有强大的抗瘙痒作用，表明钙通过 TRPV4 流入角质形成细胞中导致 ERK 磷酸化，从而迅速将角质形成细胞转化为有机瘙痒发生细胞。为了支持这一概念，我们发现由 TRPV4 直接皮内激活引起的抓挠行为严重依赖于角质形成细胞中 TRPV4 的表达。因此，TRPV4 在组胺能瘙痒中作为皮肤角质形成细胞中的瘙痒感受器-TRP 发挥作用，这是一个具有转化医学相关性的新基本概念。
TRPV4 ion channels function in epidermal keratinocytes and in innervating sensory neurons; however, the contribution of the channel in either cell to neurosensory function remains to be elucidated. We recently reported TRPV4 as a critical component of the keratinocyte machinery that responds to ultraviolet B (UVB) and functions critically to convert the keratinocyte into a pain-generator cell after excess UVB exposure. One key mechanism in keratinocytes was increased expression and secretion of endothelin-1, which is also a known pruritogen. Here we address the question of whether TRPV4 in skin keratinocytes functions in itch, as a particular form of “forefront” signaling in non-neural cells. Our results support this novel concept based on attenuated scratching behavior in response to histaminergic (histamine, compound 48/80, endothelin-1), not non-histaminergic (chloroquine) pruritogens in Trpv4 keratinocyte-specific and inducible knock-out mice. We demonstrate that keratinocytes rely on TRPV4 for calcium influx in response to histaminergic pruritogens. TRPV4 activation in keratinocytes evokes phosphorylation of mitogen-activated protein kinase, ERK, for histaminergic pruritogens. This finding is relevant because we observed robust anti-pruritic effects with topical applications of selective inhibitors for TRPV4 and also for MEK, the kinase upstream of ERK, suggesting that calcium influx via TRPV4 in keratinocytes leads to ERK-phosphorylation, which in turn rapidly converts the keratinocyte into an organismal itch-generator cell. In support of this concept we found that scratching behavior, evoked by direct intradermal activation of TRPV4, was critically dependent on TRPV4 expression in keratinocytes. Thus, TRPV4 functions as a pruriceptor-TRP in skin keratinocytes in histaminergic itch, a novel basic concept with translational-medical relevance.