Functional recovery from desensitization of vanilloid receptor TRPV1 requires resynthesis of phosphatidylinositol 4,5-bisphosphate
Functional recovery from desensitization of vanilloid receptor TRPV1 requires resynthesis of phosphatidylinositol 4,5-bisphosphate
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DOI：
10.1523/jneurosci.1296-05.2005
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发表时间：
2005-05-11
影响因子：
5.3
通讯作者：
Qin, F
中科院分区：
文献类型：
--
作者：
Liu, BY;Zhang, CG;Qin, F
辣椒素和其他天然存在的刺激性分子长期以来一直被用作局部镇痛剂来治疗各种慢性疼痛状况。这些化合物的镇痛作用涉及伤害感受器在强刺激后的长期脱敏。为了阐明潜在的机制，我们研究了从香草素受体TRPV 1的脱敏中恢复。我们发现，辣椒素的长期应用导致几乎完全脱敏的通道，其功能恢复脱敏需要高浓度的细胞内ATP。不可水解的ATP类似物不能代替ATP来促进恢复。无论是抑制或激活蛋白激酶阻止恢复的通道脱敏。相反，脂质激酶，特别是磷脂酰肌醇-4-激酶的阻断，废除恢复，如刺激磷脂酰肌醇4，5-二磷酸（PIP 2）水解的膜受体的激活。使用PIP 2敏感性内向整流钾通道Kir2.1作为生物传感器的其他实验显示了辣椒素刺激后功能抑制和随后恢复的两个通道之间的高度时间相关性。这些数据表明，PIP 2的消耗伴随着TRPV 1的激活而发生，并且其在膜中的补充决定了通道从脱敏中的恢复。除了揭示磷酸肌醇信号在调节伤害感受中的新作用外，我们的研究结果还为辣椒素镇痛作用的局部机制和提高其有效性的策略提供了新的见解。
Capsaicin and other naturally occurring pungent molecules have long been used as topical analgesics to treat a variety of chronic pain conditions. The analgesic effects of these compounds involve long- term desensitization of nociceptors after strong stimulation. To elucidate the underlying mechanisms, we studied the recovery from desensitization of the vanilloid receptor TRPV1. We showed that prolonged applications of capsaicin led to nearly complete desensitization of the channel and that its functional recovery from desensitization required a high concentration of intracellular ATP. Nonhydrolyzable ATP analogs did not substitute for ATP to promote recovery. Neither inhibition nor activation of protein kinases prevented recovery of the channel from desensitization. In contrast, blockade of lipid kinases, in particular phosphatidylinositol- 4- kinase, abolished recovery, as did activation of membrane receptors that stimulate hydrolysis of phosphatidylinositol 4,5- biphosphate ( PIP2). Additional experiments using the PIP2- sensitive inward rectifier potassium channel Kir2.1 as a biosensor showed a high degree of temporal correlation between the two channels on both functional suppression after capsaicin stimulation and subsequent recovery. These data suggest that depletion of PIP2 occurs concomitantly with activation of TRPV1 and its replenishment in the membrane determines recovery of the channel from desensitization. In addition to revealing a new role of phosphoinositide signaling in regulation of nociception, our results provide novel insight into the topical mechanisms of the analgesic effects of capsaicin and the strategies to improve its effectiveness.