Sensitization of small-diameter sensory neurons is controlled by TRPV1 and TRPA1 association.
Sensitization of small-diameter sensory neurons is controlled by TRPV1 and TRPA1 association.
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DOI：
10.1096/fj.201902026r
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发表时间：
2020-01
期刊：
影响因子：
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通讯作者：
Akopian AN
中科院分区：
文献类型：
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作者：
Patil MJ;Salas M;Bialuhin S;Boyd JT;Jeske NA;Akopian AN
感觉神经元亚型的独特特征表现为其不同的生理和病理生理功能。通过膜片钳电生理学、Ca2+成像、组织CGRP释放测定、蛋白质生物化学方法和疼痛模型的行为生理学，本研究表明，感觉神经元病理生理学的多样性部分是由于TRPV1和TRPA1的亚型依赖性致敏。差异致敏受炎症介质不同表达的影响，如前列腺素E2 （PGE2）、缓激素（BK）和神经生长因子（NGF）以及多种激酶，包括蛋白激酶A （PKA）和C （PKC）。然而，TRPA1与TRPV1的共表达和相互作用被证明是感觉神经元差异致敏的最关键因素。我们发现TRPV1上的N端和c端结构域负责TRPA1-TRPV1 （A1-V1）复合物的形成。针对这些结构域的优势负肽的A1-V1复合物的消融大大降低了TRPA1的致敏性，以及BK-和cfa诱导的超敏性。这些数据表明，经常发生的TRP通道复合物调节神经元致敏的多样性，并可能为许多神经炎症性疼痛疾病提供治疗靶点。
Unique features of sensory neuron subtypes are manifest by their distinct physiological and pathophysiological functions. Using patch-clamp electrophysiology, Ca2+ imaging, CGRP release assay from tissues, protein biochemistry approaches and behavioral physiology on pain models, this study demonstrates the diversity of sensory neuron pathophysiology is due in part to subtype-dependent sensitization of TRPV1 and TRPA1. Differential sensitization is influenced by distinct expression of inflammatory mediators, such as prostaglandin E2 (PGE2), bradykinin (BK) and nerve growth factor (NGF) as well as multiple kinases, including protein kinase A (PKA) and C (PKC). However, the co-expression and interaction of TRPA1 with TRPV1 proved to be most critical for differential sensitization of sensory neurons. We identified N- and C-terminal domains on TRPV1 responsible for TRPA1-TRPV1 (A1–V1) complex formation. Ablation of A1–V1 complex with dominant negative peptides against these domains substantially reduced sensitization of TRPA1, as well as BK- and CFA-induced hypersensitivity. These data indicate that often occurring TRP channel complexes regulate diversity in neuronal sensitization and may provide a therapeutic target for many neuro-inflammatory pain conditions.