Cyclin-Dependent Kinase 5 Controls TRPV1 Membrane Trafficking and the Heat Sensitivity of Nociceptors through KIF13B
Cyclin-Dependent Kinase 5 Controls TRPV1 Membrane Trafficking and the Heat Sensitivity of Nociceptors through KIF13B
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周期蛋白依赖性激酶 5 通过 KIF13B 控制 TRPV1 膜运输和伤害感受器的热敏感性
DOI：
10.1523/jneurosci.1634-12.2012
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发表时间：
2012-10-17
影响因子：
5.3
通讯作者：
Wang, Yun
中科院分区：
文献类型：
--
作者：
Xing, Bao-Ming;Yang, Yan-Rui;Wang, Yun
表面，特别是初级感觉神经元外周末梢的功能性瞬时受体电位香草样蛋白1 （TRPV1）通道的数量调节热敏性，TRPV1的表面定位增加有助于热痛觉过敏。然而，调控TRPV1表面定位的机制基本上是未知的。在这里，我们发现周期蛋白依赖性激酶5 (Cdk5)，热痛觉的新参与者，积极调节TRPV1表面定位。活性Cdk5在体内可促进TRPV1的顺行运输，提示Cdk5在TRPV1膜运输中具有调节作用。含有trpv1的囊泡与KIF13B（激酶3家族成员13B）的叉头相关（FHA）结构域结合，从而被递送到细胞表面。Cdk5或其激活剂p35的过表达促进了KIF13B-TRPV1的关联，而Cdk5活性的抑制阻止了KIF13B-TRPV1的关联，这表明Cdk5通过介导车货关联促进了TRPV1的顺行运输。Cdk5磷酸化KIF13B位于FHA结构域的Thr-506残基。T506A突变降低了动力-货物相互作用和细胞渗透性TAT-T506肽，靶向Thr-506，降低了TRPV1的表面定位，表明Thr-506磷酸化在TRPV1运输中起重要作用。此外，完全弗氏佐剂（CFA）注射诱导的Cdk5激活增加了trpv1的顺行运输，促进了热痛觉过敏的发生并可能维持，而鞘内给药TAT-T506肽减轻了CFA诱导的大鼠热痛觉过敏。因此，Cdk5调控TRPV1膜运输是控制伤害感受器热敏性的基本机制，炎症期间适度抑制Thr-506磷酸化可能有助于治疗炎症性热痛。
The number of functional transient receptor potential vanilloid 1 (TRPV1) channels at the surface, especially at the peripheral terminals of primary sensory neurons, regulates heat sensitivity, and increased surface localization of TRPV1s contributes to heat hyperalgesia. However, the mechanisms for regulating TRPV1 surface localization are essentially unknown. Here, we show that cyclin-dependent kinase 5 (Cdk5), a new player in thermal pain sensation, positively regulates TRPV1 surface localization. Active Cdk5 was found to promote TRPV1 anterograde transport in vivo, suggesting a regulatory role of Cdk5 in TRPV1 membrane trafficking. TRPV1-containing vesicles bind to the forkhead-associated (FHA) domain of the KIF13B (kinesin-3 family member 13B) and are thus delivered to the cell surface. Overexpression of Cdk5 or its activator p35 promoted and inhibition of Cdk5 activity prevented the KIF13B–TRPV1 association, indicating that Cdk5 promotes TRPV1 anterograde transport by mediating the motor–cargo association. Cdk5 phosphorylates KIF13B at Thr-506, a residue located in the FHA domain. T506A mutation reduced the motor–cargo interaction and the cell-permeable TAT–T506 peptide, targeting to the Thr-506, decreased TRPV1 surface localization, demonstrating the essential role of Thr-506 phosphorylation in TRPV1 transport. Moreover, complete Freund's adjuvant (CFA) injection-induced activation of Cdk5 increased the anterograde transport of TRPV1s, contributing to the development and possibly the maintenance of heat hyperalgesia, whereas intrathecal delivery of the TAT–T506 peptide alleviated CFA-induced heat hyperalgesia in rats. Thus, Cdk5 regulation of TRPV1 membrane trafficking is a fundamental mechanism controlling the heat sensitivity of nociceptors, and moderate inhibition of Thr-506 phosphorylation during inflammation might be helpful for the treatment of inflammatory thermal pain.