KChIP3 N-Terminal 31-50 Fragment Mediates Its Association with TRPV1 and Alleviates Inflammatory Hyperalgesia in Rats
KChIP3 N-Terminal 31-50 Fragment Mediates Its Association with TRPV1 and Alleviates Inflammatory Hyperalgesia in Rats
复制标题
KChIP3 N 末端 31-50 片段介导其与 TRPV1 的关联并减轻大鼠炎症性痛觉过敏
DOI：
10.1523/jneurosci.2242-17.2018
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发表时间：
2018-02-14
影响因子：
5.3
通讯作者：
Zhang, Ying
中科院分区：
文献类型：
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作者：
Tian, Na-Xi;Xu, Yu;Zhang, Ying
钾电压门控通道相互作用蛋白3 (KChIP3)，也称为下游调控元件拮抗剂调节剂（DREAM）和钙senilin，是一种属于神经元钙传感器（NCS）家族的多功能蛋白。最近的研究发现KChIP3在背根神经节（DRG）神经元中表达，提示KChIP3在外周感觉加工中的潜在作用。在本研究中，我们发现KChIP3与瞬时受体电位离子通道V1 （TRPV1）共定位，TRPV1是炎症疼痛过程中参与外周致敏的关键分子。此外，KChIP3的N端31-50片段能够结合TRPV1的细胞内N端和C端，这大大降低了TRPV1的表面定位和随后通过通道的Ca2+内流。重要的是，在一个完全的弗氏佐剂诱导的雄性大鼠炎症性疼痛模型中，鞘内给药跨膜肽转录反激活因子(TAT)-31-50显著减少Ca2+通过TRPV1在DRG神经元内的内流，减轻热痛觉过敏和步态改变。此外，足底注射TAT-31-50可减弱辣椒素诱发的自发性疼痛行为和热痛觉过敏，进一步增强了TAT-31-50对TRPV1通道的调节作用。此外，TAT-31-50还能减轻本研究产生的kcnip3−/−大鼠的炎症性热痛觉过敏，提示TAT-31-50介导的镇痛作用不依赖于内源性KChIP3。我们的研究揭示了KChIP3镇痛功能的一种新的外周机制，并提供了一种潜在的止痛剂TAT-31-50，用于治疗炎症性疼痛。由炎症或损伤组织引起的炎症性疼痛显著影响患者的生活质量。本研究旨在阐明外周钾通道相互作用蛋白3 （KChIP3）在炎症性疼痛中的作用。KChIP3 n端31-50片段与瞬时受体电位离子通道V1 （TRPV1）直接相互作用。KChIP3-TRPV1的相互作用减少了TRPV1的表面定位，从而减轻了外周炎症引起的热痛觉过敏和步态改变。此外，跨膜转录反激活因子(TAT)-31-50肽显示出独立于内源性KChIP3的炎症性痛觉过敏的镇痛作用。这项工作揭示了外周KChIP3在炎性痛觉过敏中的新机制，不同于它在疼痛调节中作为转录抑制因子的经典作用。
Potassium voltage-gated channel interacting protein 3 (KChIP3), also termed downstream regulatory element antagonist modulator (DREAM) and calsenilin, is a multifunctional protein belonging to the neuronal calcium sensor (NCS) family. Recent studies revealed the expression of KChIP3 in dorsal root ganglion (DRG) neurons, suggesting the potential role of KChIP3 in peripheral sensory processing. Herein, we show that KChIP3 colocalizes with transient receptor potential ion channel V1 (TRPV1), a critical molecule involved in peripheral sensitization during inflammatory pain. Furthermore, the N-terminal 31-50 fragment of KChIP3 is capable of binding both the intracellular N and C termini of TRPV1, which substantially decreases the surface localization of TRPV1 and the subsequent Ca2+ influx through the channel. Importantly, intrathecal administration of the transmembrane peptide transactivator of transcription (TAT)-31-50 remarkably reduces Ca2+ influx via TRPV1 in DRG neurons and alleviates thermal hyperalgesia and gait alterations in a complete Freund's adjuvant-induced inflammatory pain model in male rats. Moreover, intraplantar injection of TAT-31-50 attenuated the capsaicin-evoked spontaneous pain behavior and thermal hyperalgesia, which further strengthened the regulatory role of TAT-31-50 on TRPV1 channel. In addition, TAT-31-50 could also alleviate inflammatory thermal hyperalgesia in kcnip3−/− rats generated in our study, suggesting that the analgesic effect mediated by TAT-31-50 is independent of endogenous KChIP3. Our study reveals a novel peripheral mechanism for the analgesic function of KChIP3 and provides a potential analgesic agent, TAT-31-50, for the treatment of inflammatory pain. SIGNIFICANCE STATEMENT Inflammatory pain arising from inflamed or injured tissues significantly compromises the quality of life in patients. This study aims to elucidate the role of peripheral potassium channel interacting protein 3 (KChIP3) in inflammatory pain. Direct interaction of the KChIP3 N-terminal 31-50 fragment with transient receptor potential ion channel V1 (TRPV1) was demonstrated. The KChIP3–TRPV1 interaction reduces the surface localization of TRPV1 and thus alleviates heat hyperalgesia and gait alterations induced by peripheral inflammation. Furthermore, the transmembrane transactivator of transcription (TAT)-31-50 peptide showed analgesic effects on inflammatory hyperalgesia independently of endogenous KChIP3. This work reveals a novel mechanism of peripheral KChIP3 in inflammatory hyperalgesia that is distinct from its classical role as a transcriptional repressor in pain modulation.