Avenali Luca, Narayanan Pratibha, Rouwette Tom, Cervellini Ilaria, Sereda Michael, Gomez-Varela David, Schmidt Manuela
Somatosensory Signalling Group and.
Department of Neurogenetics, Max Planck Institute of Experimental Medicine, D-37075 Goettingen, Germany.
J Neurosci. 2014 Oct 29;34(44):14506-16. doi: 10.1523/JNEUROSCI.1801-14.2014.
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.
瞬时受体电位A1（TRPA1）通道对脊椎动物的疼痛至关重要。尽管对配体激活TRPA1的研究已很广泛，但对调节TRPA1的分子机制却知之甚少。我们采用基于蛋白质组学的无偏向性方法，发现膜联蛋白A2（AnxA2）与小鼠感觉神经元中的天然TRPA1存在物理关联。AnxA2在感觉神经元的一个亚群中富集，并与TRPA1共表达。此外，我们观察到来自AnxA2缺陷小鼠的培养感觉神经元中TRPA1膜水平增加。这在我们的钙成像实验中得到体现，该实验显示AnxA2缺陷神经元在TRPA1激活后具有更高的反应性。在体内，这些发现与在急性和炎性疼痛的TRPA1依赖性模式中增强的伤害性防御行为相关，而AnxA2缺陷小鼠的热敏感性、机械敏感性以及TRPV1介导的疼痛则得以保留。我们的结果支持一种模型，即AnxA2通过限制TRPA1通道的可用性来调节脊椎动物的伤害性信号传导。
