Inhibition of heat shock protein 90 attenuates adenylate cyclase sensitization after chronic morphine treatment
Inhibition of heat shock protein 90 attenuates adenylate cyclase sensitization after chronic morphine treatment
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DOI：
10.1016/j.bbrc.2010.01.089
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发表时间：
2010-02-19
影响因子：
3.1
通讯作者：
Fujimura, Akio
中科院分区：
文献类型：
--
作者：
Koshimizu, Taka-aki;Tsuchiya, Hiroyoshi;Fujimura, Akio
细胞对慢性阿片类药物治疗的适应性导致腺苷环化酶的反应性增强，并增加Forsklin或激动剂刺激的cAMP产生。然而，尚不清楚热休克蛋白等伴侣分子是否有助于腺苷环化酶的敏化。在这里，我们报告了热休克蛋白90(Hsp90)的抑制剂格尔达那霉素处理细胞后，有效地减弱了吗啡诱导的腺苷环化酶敏化。在SK-N-SH人神经母细胞瘤细胞中，吗啡显著增加I型腺苷环化酶的RNA转录和蛋白水平，从而导致致敏。全基因组芯片分析表明，cAMP反应元件结合蛋白不仅在SK-N-SH细胞中与Hsp90AB1的近端启动子相关，而且在大鼠PC12和人胚胎肾细胞中也与Hsp90AB1的启动子相关。在吗啡处理过程中，Hsp90AB1的转录和蛋白水平显著增加，联合应用格尔达霉素(0.1-10 nm)可有效地抑制Forsklin激活的腺苷酸环化酶激活的增加56%。在格尔达霉素治疗期间，I型腺苷环化酶，而不是Hsp90AB1，发生了显著的降解。这些结果表明，Hsp90是抑制慢性吗啡诱导的腺苷环化酶敏化的一个新的药理靶点。(C)2010 Elsevier Inc.保留所有权利。
Cellular adaptations to chronic opioid treatment result in enhanced responsiveness of adenylate cyclase and an increase in forskolin- or agonist-stimulated cAMP production. It is, however, not known whether chaperone molecules such as heat shock proteins contribute to this adenylate cyclase sensitization. Here, we report that treatment of cells with geldanamycin, an inhibitor of heat shock protein 90 (Hsp90), led to effective attenuation of morphine-induced adenylate cyclase sensitization. In SK-N-SH human neuroblastoma cells, morphine significantly increased RNA transcript and protein levels of type I adenylate cyclase, leading to sensitization. Whole-genome tiling array analysis revealed that cAMP response element-binding protein, an important mediator for cellular adaptation to morphine, associated with the proximal promoter of Hsp90AB1 not only in SK-N-SH cells but also in rat PC12 and human embryonic kidney cells. Hsp90AB1 transcript and protein levels increased significantly during morphine treatment, and co-application of geldanamycin (0.1-10nM) effectively suppressed the increase in forskolin-activated adenylate cyclase activation by 56%. Type I adenylate cyclase, but not Hsp90AB1, underwent significant degradation during geldanamycin treatment. These results indicate that Hsp90 is a new pharmacological target for the suppression of adenylate cyclase sensitization induced by chronic morphine treatment. (C) 2010 Elsevier Inc. All rights reserved.