TNFα induces co-trafficking of TRPV1/TRPA1 in VAMP1-containing vesicles to the plasmalemma via Munc18-1/syntaxin1/SNAP-25 mediated fusion.
TNFα induces co-trafficking of TRPV1/TRPA1 in VAMP1-containing vesicles to the plasmalemma via Munc18-1/syntaxin1/SNAP-25 mediated fusion.
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DOI：
10.1038/srep21226
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发表时间：
2016-02-18
影响因子：
4.6
通讯作者：
Dolly JO
中科院分区：
文献类型：
--
作者：
Meng J;Wang J;Steinhoff M;Dolly JO
瞬时受体电位（TRP）A1和V1通道传递感觉信号，但对炎症过程中它们向质膜的转运知之甚少。在本文中，TRPA 1和TRPV 1被发现在含有降钙素基因相关肽（CGRP）的囊泡上，在胞吞作用和胞吞作用的位点积累，并且共同定位在表达两者的培养的感觉神经元的纤维和细胞体上。促炎细胞因子TNFα升高了它们的表面含量，并且两者紧密靠近，表明共同运输。事实证明，突触融合蛋白1相互作用蛋白Munc 18 -1对于对TNFα的反应和TRPV 1触发的CGRP释放是必需的。TNFα诱导的TRPV 1和TRPA 1表面运输需要突触囊泡膜蛋白VAMP 1（但不是2/3），这对于大致密核心囊泡的CGRP胞吐至关重要。通过肉毒杆菌神经毒素（BoNT）/C1或/A灭活突触前质膜上的两种蛋白质，syntaxin-1或SNAP-25，抑制TNFα升高的递送。因此，BoNT/A消除了TNFα通过上调的表面表达的TRPV 1和TRPA 1通道增强的Ca 2+内流。因此，此外，神经毒素已知抑制疼痛递质的释放，其治疗潜力通过降低转导通道的胞吐递送和由此产生的炎症超敏作用而增强。
Transient receptor potential (TRP) A1 and V1 channels relay sensory signals, yet little is known about their transport to the plasmalemma during inflammation. Herein, TRPA1 and TRPV1 were found on vesicles containing calcitonin gene-related peptide (CGRP), accumulated at sites of exo- and endo-cytosis, and co-localised on fibres and cell bodies of cultured sensory neurons expressing both. A proinflammatory cytokine, TNFα, elevated their surface content, and both resided in close proximity, indicating co-trafficking. Syntaxin 1–interacting protein, Munc18–1, proved necessary for the response to TNFα, and for TRPV1-triggered CGRP release. TNFα-induced surface trafficking of TRPV1 and TRPA1 required a synaptic vesicle membrane protein VAMP1 (but not 2/3), which is essential for CGRP exocytosis from large dense-core vesicles. Inactivation of two proteins on the presynaptic plasma membrane, syntaxin-1 or SNAP-25, by botulinum neurotoxin (BoNT)/C1 or /A inhibited the TNFα-elevated delivery. Accordingly, enhancement by TNFα of Ca2+ influx through the upregulated surface-expressed TRPV1 and TRPA1 channels was abolished by BoNT/A. Thus, in addition, the neurotoxins’ known inhibition of the release of pain transmitters, their therapeutic potential is augmented by lowering the exocytotic delivery of transducing channels and the resultant hyper-sensitisation in inflammation.