Anti-calmodulins and tricyclic adjuvants in pain therapy block the TRPV1 channel.
Anti-calmodulins and tricyclic adjuvants in pain therapy block the TRPV1 channel.
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DOI：
10.1371/journal.pone.0000545
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发表时间：
2007-06-20
期刊：
影响因子：
3.7
通讯作者：
Vizler C
中科院分区：
文献类型：
--
作者：
Oláh Z;Jósvay K;Pecze L;Letoha T;Babai N;Budai D;Otvös F;Szalma S;Vizler C
在细胞内Ca 2+危险升高时，负载Ca 2+的钙调蛋白通常抑制多个Ca 2+通道，并保护细胞免受Ca 2+细胞毒性，因此理论上阻断钙调蛋白应导致细胞内Ca 2+不受控制的升高。有趣的是，经典的抗精神病药物，抗钙调蛋白药物在这里被注意到通过香草素诱导的Ca 2+通道/炎性疼痛受体1（TRPV 1）抑制Ca 2+摄取，这表明钙调蛋白抑制剂可以阻断孔形成和Ca 2+进入。对TRPV 1表达细胞的功能测定支持在μM浓度下对香草素诱导的45 Ca 2+摄取的直接、剂量依赖性抑制：钙咪达唑鎓（宽范围）≥三氟拉嗪（窄范围）>氯丙嗪/阿米替林>氟奋乃静>>W-7和W-13（仅部分）。最有可能的是，在通道口的孔环处的短酸性结构域充当Ca 2+或抗钙调蛋白药物的结合位点。钙调素的选择性肽阻断剂Camstatin抑制香草醛诱导的完整TRPV 1+细胞中的Ca 2+摄取，并提示细胞外抑制位点。TRPV 1+，来自感觉神经节的炎性疼痛赋予伤害性感受神经元，被各种抗精神病药和抗钙调素药物阻断。其中，calmidazolium，最有效的钙调素激动剂，阻断Ca 2+进入的非竞争性动力学，影响TRPV 1在不同的网站比香草素结合口袋。数据表明，各种钙调素拮抗剂对接到细胞外的网站，没有发现在其他Ca 2+通道。钙调素拮抗剂诱发的TRPV 1和NMDA受体/Ca ~（2+）通道的抑制作用通过钙咪唑对椎板切除大鼠的细胞外单单位记录的体内监测进行验证。这些意想不到的发现可以解释经验上注意到的临床疼痛辅助治疗的疗效，证明努力开发成止痛药，选择性感觉钙通道，但不影响运动神经元。
Ca2+-loaded calmodulin normally inhibits multiple Ca2+-channels upon dangerous elevation of intracellular Ca2+ and protects cells from Ca2+-cytotoxicity, so blocking of calmodulin should theoretically lead to uncontrolled elevation of intracellular Ca2+. Paradoxically, classical anti-psychotic, anti-calmodulin drugs were noted here to inhibit Ca2+-uptake via the vanilloid inducible Ca2+-channel/inflamatory pain receptor 1 (TRPV1), which suggests that calmodulin inhibitors may block pore formation and Ca2+ entry. Functional assays on TRPV1 expressing cells support direct, dose-dependent inhibition of vanilloid-induced 45Ca2+-uptake at µM concentrations: calmidazolium (broad range)≥trifluoperazine (narrow range)>chlorpromazine/amitriptyline>fluphenazine>>W-7 and W-13 (only partially). Most likely a short acidic domain at the pore loop of the channel orifice functions as binding site either for Ca2+ or anti-calmodulin drugs. Camstatin, a selective peptide blocker of calmodulin, inhibits vanilloid-induced Ca2+-uptake in intact TRPV1+ cells, and suggests an extracellular site of inhibition. TRPV1+, inflammatory pain-conferring nociceptive neurons from sensory ganglia, were blocked by various anti-psychotic and anti-calmodulin drugs. Among them, calmidazolium, the most effective calmodulin agonist, blocked Ca2+-entry by a non-competitive kinetics, affecting the TRPV1 at a different site than the vanilloid binding pocket. Data suggest that various calmodulin antagonists dock to an extracellular site, not found in other Ca2+-channels. Calmodulin antagonist-evoked inhibition of TRPV1 and NMDA receptors/Ca2+-channels was validated by microiontophoresis of calmidazolium to laminectomised rat monitored with extracellular single unit recordings in vivo. These unexpected findings may explain empirically noted efficacy of clinical pain adjuvant therapy that justify efforts to develop hits into painkillers, selective to sensory Ca2+-channels but not affecting motoneurons.
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影响因子：
3.4
作者：
Del Carlo, B;Pellegrini, M;Pellegrino, M
通讯作者：
Pellegrino, M
影响因子：
2.9
作者：
Kitaguchi, T;Swartz, KJ
通讯作者：
Swartz, KJ
影响因子：
64.5
作者：
Jordt, SE;Julius, D
通讯作者：
Julius, D
DOI：
10.1073/pnas.100129497
发表时间：
2000-07-05
影响因子：
11.1
作者：
Jordt, SE;Tominaga, M;Julius, D
通讯作者：
Julius, D
影响因子：
9.9
作者：
Kieburtz, K;Simpson, D;Cohen, B
通讯作者：
Cohen, B