Protease activated receptors 1 and 4 sensitize TRPV1 in nociceptive neurones.
Protease activated receptors 1 and 4 sensitize TRPV1 in nociceptive neurones.
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DOI：
10.1186/1744-8069-6-61
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发表时间：
2010-09-27
期刊：
影响因子：
3.3
通讯作者：
McNaughton PA
中科院分区：
文献类型：
--
作者：
Vellani V;Kinsey AM;Prandini M;Hechtfischer SC;Reeh P;Magherini PC;Giacomoni C;McNaughton PA
蛋白酶激活受体（PAR1-4）被细胞损伤或血液凝固释放的蛋白酶激活，已知参与促进疼痛和痛觉过敏。先前的研究表明，PAR2受体增强了TRPV1的激活，但其他PARs的作用尚不清楚。本文研究了凝血酶激活受体PAR1、3和4在感觉神经元中的表达和功能。免疫细胞化学和原位杂交显示，PAR1和PAR4在10 - 15%的神经元中表达，分布在所有大小类别中。凝血酶或特定的PAR1或PAR4激活肽（PAR1/4- ap）引起PLCβ/PKC途径激活的功能效应：细胞内钙释放、TRPV1的致敏和PKC的epsilon亚型（PKCε）向神经元细胞膜的易位。PKC抑制剂显著降低了TRPV1的致敏作用。对凝血酶或PAR1-AP有反应的神经元要么是肽能亚类的小伤害性神经元，要么是表达髓鞘纤维标记物的大神经元。PAR1-AP和PAR4- ap的连续应用表明，PAR4在par1表达神经元的一个子集中表达。相比之下，钙对PAR2-AP的反应在不同的小IB4+伤害感觉神经元群体中可见。PAR3在感觉神经元中似乎没有功能。在皮肤神经制剂中，PAR1-AP能增强热敏作用下神经肽CGRP的释放。神经生长因子（NGF）培养增加了IB4-群体中凝血酶反应神经元的比例，而胶质源性神经营养因子（GDNF）和neurturin则上调了IB4+群体中凝血酶反应神经元的比例。我们得出结论，PAR1和PAR4在大髓鞘纤维神经元中有功能表达，并且也在肽能亚类的小伤害感受器中表达，其中它们能够增强TRPV1的活性。
Protease-activated receptors (PAR1-4) are activated by proteases released by cell damage or blood clotting, and are known to be involved in promoting pain and hyperalgesia. Previous studies have shown that PAR2 receptors enhance activation of TRPV1 but the role of other PARs is less clear. In this paper we investigate the expression and function of the PAR1, 3 and 4 thrombin-activated receptors in sensory neurones. Immunocytochemistry and in situ hybridization show that PAR1 and PAR4 are expressed in 10 - 15% of neurons, distributed across all size classes. Thrombin or a specific PAR1 or PAR4 activating peptide (PAR1/4-AP) caused functional effects characteristic of activation of the PLCβ/PKC pathway: intracellular calcium release, sensitisation of TRPV1, and translocation of the epsilon isoform of PKC (PKCε) to the neuronal cell membrane. Sensitisation of TRPV1 was significantly reduced by PKC inhibitors. Neurons responding to thrombin or PAR1-AP were either small nociceptive neurones of the peptidergic subclass, or larger neurones which expressed markers for myelinated fibres. Sequential application of PAR1-AP and PAR4-AP showed that PAR4 is expressed in a subset of the PAR1-expressing neurons. Calcium responses to PAR2-AP were by contrast seen in a distinct population of small IB4+ nociceptive neurones. PAR3 appears to be non-functional in sensory neurones. In a skin-nerve preparation the release of the neuropeptide CGRP by heat was potentiated by PAR1-AP. Culture with nerve growth factor (NGF) increased the proportion of thrombin-responsive neurons in the IB4- population, while glial-derived neurotropic factor (GDNF) and neurturin upregulated the proportion of thrombin-responsive neurons in the IB4+ population. We conclude that PAR1 and PAR4 are functionally expressed in large myelinated fibre neurons, and are also expressed in small nociceptors of the peptidergic subclass, where they are able to potentiate TRPV1 activity.
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影响因子：
3.4
作者：
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通讯作者：
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影响因子：
5.5
作者：
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影响因子：
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作者：
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