Annexin A2 Regulates TRPA1-Dependent Nociception
Annexin A2 Regulates TRPA1-Dependent Nociception
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DOI：
10.1523/jneurosci.1801-14.2014
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发表时间：
2014-10-29
影响因子：
5.3
通讯作者：
Schmidt, Manuela
中科院分区：
文献类型：
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作者：
Avenali, Luca;Narayanan, Pratibha;Schmidt, Manuela
瞬时受体电位A1（TRPA1）通道是脊椎动物疼痛所必需的。尽管TRPA1激活配体已被广泛研究，调节TRPA1的分子机制知之甚少。使用无偏的基于蛋白质组学的方法，我们发现了小鼠感觉神经元中Annexin A2（AnxA2）与天然TRPA 1的物理关联。AnxA2在感觉神经元亚群中富集，并与TRPA 1共表达。此外，我们观察到增加TRPA1膜水平在培养的感觉神经元AnxA2缺陷小鼠。我们的钙成像实验反映了这一点，该实验揭示了AnxA2缺陷神经元对TRPA1激活的更高响应性。在体内，这些发现与TRPA1依赖的急性和炎性疼痛范式中的伤害反应行为增强有关，而AnxA2缺陷小鼠中保留了热和机械敏感性以及TRPV1介导的疼痛。我们的研究结果支持一个模型，即AnxA2限制TRPA1通道的可用性，以调节脊椎动物的伤害性信号。
The transient receptor potential A1 (TRPA1) channel is essential for vertebrate pain. Even though TRPA1 activation by ligands has been studied extensively, the molecular machinery regulating TRPA1 is only poorly understood. Using an unbiased proteomics-based approach we uncovered the physical association of Annexin A2 (AnxA2) with native TRPA1 in mouse sensory neurons. AnxA2 is enriched in a subpopulation of sensory neurons and coexpressed with TRPA1. Furthermore, we observe an increase of TRPA1 membrane levels in cultured sensory neurons from AnxA2-deficient mice. This is reflected by our calcium imaging experiments revealing higher responsiveness upon TRPA1 activation in AnxA2-deficient neurons. In vivo these findings are associated with enhanced nocifensive behaviors specifically in TRPA1-dependent paradigms of acute and inflammatory pain, while heat and mechanical sensitivity as well as TRPV1-mediated pain are preserved in AnxA2-deficient mice. Our results support a model whereby AnxA2 limits the availability of TRPA1 channels to regulate nociceptive signaling in vertebrates.