Cisplatin causes over-expression of tachykinin NK1 receptors and increases ERK1/2- and PKA phosphorylation during peak immediate- and delayed-phase emesis in the least shrew (Cryptotis parva) brainstem
Cisplatin causes over-expression of tachykinin NK1 receptors and increases ERK1/2- and PKA phosphorylation during peak immediate- and delayed-phase emesis in the least shrew (Cryptotis parva) brainstem
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DOI：
10.1016/j.ejphar.2012.09.008
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发表时间：
2013-01-05
影响因子：
5
通讯作者：
Alkam, Tursun
中科院分区：
文献类型：
--
作者：
Darmani, Nissar A.;Dey, Dilip;Alkam, Tursun
关于顺铂诱导呕吐期间顺铂对速激肽 NK1 受体表达谱和下游信号传导的影响的信息很少。顺铂在注射后 1-2 小时和 33 小时引起最小鼩鼱的早期和延迟期呕吐高峰。为了研究 NK1 受体在两个催吐阶段的表达谱，我们克隆了对应于类似 700 个碱基对的 mRNA 的 cDNA，两侧是不同物种间保守的两段核苷酸，并证明鼩鼱 NK1 受体核苷酸序列与人类 NK1 受体具有相似的 90% 序列同一性。在测试的12个时间点中，注射顺铂后2小时和28小时，鼩鼱脑干中NK1受体mRNA表达水平显着增加，而肠道NK1受体mRNA在28小时增加。鼩鼱脑干和肠道 P 物质 mRNA 水平在这两个阶段也趋于增加。此外，顺铂治疗后2、8和33小时，脑干中NK1受体蛋白的表达水平显着增加。未观察到脑干 5-HT (3) 受体蛋白表达的变化。顺铂治疗后 2、8 和 33 小时脑干 ERK1/2 磷酸化状态的显着增加反映了 NK1 受体蛋白表达的暂时增强。 PKA 的磷酸化在第 33 小时和第 40 小时显着增加。我们的结果表明顺铂的峰值即刻期和延迟期呕吐频率与以下因素相关：(1) NK1 受体 mRNA 的表达水平及其蛋白质水平，以及 (2) 下游 NK1 受体介导的 ERK1/2 和 PKA 信号磷酸化。 (C) 2012 Elsevier B.V. 保留所有权利。
Scant information is available regarding the effects of cisplatin on the expression profile of tachykinin NK1 receptors and downstream signaling during cisplatin-induced emesis. Cisplatin causes peak early- and delayed-phase emesis in the least shrew at 1-2 and 33 h post-injection. To investigate the expression profile of NK1 receptor during both emetic phases, we cloned the cDNA corresponding to a similar to 700 base pairs of mRNA flanked by two stretches of nucleotides conserved among different species and demonstrated that the shrew NK1 receptor nucleotide sequence shares similar to 90% sequence identity with the human NK1 receptor. Of the 12 time-points tested, significant increases in expression levels of NK1 receptor mRNA in the shrew brainstem occurred at 2 and 28 h post-cisplatin injection, whereas intestinal NK1 receptor mRNA was increased at 28 h. Shrew brainstem and intestinal substance P mRNA levels also tended to increase during the two phases. Furthermore, expression levels of NK1 receptor protein were significantly increased in the brainstem at 2, 8, and 33 h post-cisplatin. No change in brainstem 5-HT (3) receptor protein expression was observed. The temporal enhancements in NK1 receptor protein expression were mirrored by significant increases in the phosphorylation status of the brainstem ERK1/2 at 2, 8, and 33 h post-cisplatin. Phosphorylation of PKA significantly increased at 33rd and 40th hour. Our results indicate associations between cisplatin's peak immediate- and delayed-phase vomiting frequency with increased: (1) expression levels of NK1 receptor mRNA and its protein level, and (2) downstream NK1 receptor-mediated phosphorylation of ERK1/2 and PKA signaling. (C) 2012 Elsevier B.V. All rights reserved.