Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins
Sensitization of TRPV1 by EP1 and IP reveals peripheral nociceptive mechanism of prostaglandins
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DOI：
10.1186/1744-8069-1-3
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发表时间：
2005-01-17
期刊：
影响因子：
3.3
通讯作者：
Tominaga, Makoto
中科院分区：
文献类型：
--
作者：
Moriyama, Tomoko;Higashi, Tomohiro;Tominaga, Makoto
前列腺素E-2（PGE（2））和前列腺素I-2（PGI（2））是主要的炎症介质，在疼痛感觉和痛觉过敏中起重要作用。其受体（分别为EP和IP）在炎症中的作用已得到充分证实，尽管参与该过程的EP受体亚型和潜在的细胞机制仍有待阐明。辣椒素受体TRPVI是一种非选择性阳离子通道，在感觉神经元中表达，并被各种伤害性刺激激活。据报道，TRPVI对通过PKA和PKC依赖性途径介导的炎性疼痛至关重要。PGE（2）或PGI（2-）分别以PKC依赖性方式在表达TRPVI的HEK 293细胞和小鼠DRG神经元中增加或敏化通过EP 1或IP受体的TRPVI反应。在PGE（2）或PGI（2）存在的情况下，TRPVI激活的温度阈值降低到35 ℃以下，因此接近体温的温度足以激活TRPVI。PKA依赖性途径也参与了分别暴露于PGE（2）和PGI（2）后通过EP 4和IP受体增强TRPVI的作用。在TRPVI缺陷小鼠和EP 1缺陷小鼠中，PGE（2）诱导的热痛觉过敏和炎性伤害性反应均减弱。使用TRPVI缺陷小鼠和IP缺陷小鼠也证明了IP受体参与。因此，通过EP 1或IP激活增强或敏化TRPVI活性可能是PGE（2）或PGI（2）外周伤害性作用的一个重要机制。
Prostaglandin E-2 (PGE(2)) and prostaglandin I-2 (PGI(2)) are major inflammatory mediators that play important roles in pain sensation and hyperalgesia. The role of their receptors (EP and IP, respectively) in inflammation has been well documented, although the EP receptor subtypes involved in this process and the underlying cellular mechanisms remain to be elucidated. The capsaicin receptor TRPVI is a nonselective cation channel expressed in sensory neurons and activated by various noxious stimuli. TRPVI has been reported to be critical for inflammatory pain mediated through PKA- and PKC-dependent pathways. PGE(2) or PGI(2-)increased or sensitized TRPVI responses through EP1 or IP receptors, respectively predominantly in a PKC- dependent manner in both HEK293 cells expressing TRPVI and mouse DRG neurons. In the presence of PGE(2) or PGI(2), the temperature threshold for TRPVI activation was reduced below 35 degrees C, so that temperatures near body temperature are sufficient to activate TRPVI. A PKA- dependent pathway was also involved in the potentiation of TRPVI through EP4 and IP receptors upon exposure to PGE(2) and PGI(2), respectively. Both PGE(2)- induced thermal hyperalgesia and inflammatory nociceptive responses were diminished in TRPVI-deficient mice and EP1-deficient mice. IP receptor involvement was also demonstrated using TRPVI-deficient mice and IP-deficient mice. Thus, the potentiation or sensitization of TRPVI activity through EP1 or IP activation might be one important mechanism underlying the peripheral nociceptive actions of PGE(2) or PGI(2).