LIMK-Dependent Actin Polymerization in Primary Sensory Neurons Promotes the Development of Inflammatory Heat Hyperalgesia in Rats
LIMK-Dependent Actin Polymerization in Primary Sensory Neurons Promotes the Development of Inflammatory Heat Hyperalgesia in Rats
复制标题
初级感觉神经元中 LIMK 依赖性肌动蛋白聚合促进大鼠炎症性热痛觉过敏的发生
DOI：
10.1126/scisignal.2005353
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发表时间：
2014-06-24
影响因子：
7.3
通讯作者：
Wang, Yun
中科院分区：
文献类型：
--
作者：
Li, Yi;Hu, Fang;Wang, Yun
神经元中肌动蛋白细胞骨架的变化与突触可塑性有关，也可能参与伤害感受的机制。我们发现，含有LIM基序的蛋白激酶（LIMKs），调节肌动蛋白动力学，促进炎症性痛觉过敏（对疼痛刺激过度敏感）的发展。疼痛由背根神经节（DRG）的初级感觉神经元感受。在大鼠注射完全弗氏佐剂（CFA），诱导炎性热痛觉过敏，DRG神经元表现出增加LIMK活性和磷酸化，从而抑制LIMK底物cofilin，肌动蛋白切断蛋白。操作，减少LIMK活性或丰度，防止磷酸化的cofilin，或破坏肌动蛋白丝在DRG神经元衰减CFA诱导的热痛觉过敏。炎症刺激刺激肌动蛋白聚合，并增强了阳离子通道TRPV1（瞬时受体电位V1）的反应，辣椒素在DRG神经元，这种影响被逆转的LIMK敲低或防止cofilin磷酸化。此外，炎症刺激引起TRPV1的丝氨酸磷酸化，这是通过阻止在DRG神经元中的cofilin磷酸化而消除的。我们的结论是，LIMK依赖肌动蛋白重排的初级感觉神经元，导致改变TRPV1的敏感性，参与了炎症性痛觉过敏的发展。
Changes in the actin cytoskeleton in neurons are associated with synaptic plasticity and may also be involved in mechanisms of nociception. We found that the LIM motif-containing protein kinases (LIMKs), which regulate actin dynamics, promoted the development of inflammatory hyperalgesia (excessive sensitivity to painful stimuli). Pain is sensed by the primary sensory neurons of dorsal root ganglion (DRG). In rats injected with complete Freund's adjuvant (CFA), which induces inflammatory heat hyperalgesia, DRG neurons showed an increase in LIMK activity and in the phosphorylation and thus inhibition of the LIMK substrate cofilin, an actin-severing protein. Manipulations that reduced LIMK activity or abundance, prevented the phosphorylation of cofilin, or disrupted actin filaments in DRG neurons attenuated CFA-induced heat hyperalgesia. Inflammatory stimuli stimulated actin polymerization and enhanced the response of the cation channel TRPV1 (transient receptor potential V1) to capsaicin in DRG neurons, effects that were reversed by the knockdown of LIMK or preventing cofilin phosphorylation. Furthermore, inflammatory stimuli caused the serine phosphorylation of TRPV1, which was abolished by preventing cofilin phosphorylation in DRG neurons. We conclude that LIMK-dependent actin rearrangement in primary sensory neurons, leading to altered TRPV1 sensitivity, is involved in the development of inflammatory hyperalgesia.