Overexpression of GRK6 alleviates chronic visceral hypersensitivity through downregulation of P2Y6 receptors in anterior cingulate cortex of rats with prenatal maternal stress.
Overexpression of GRK6 alleviates chronic visceral hypersensitivity through downregulation of P2Y6 receptors in anterior cingulate cortex of rats with prenatal maternal stress.
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GRK6 过度表达通过下调产前母性应激大鼠前扣带皮层 P2Y6 受体缓解慢性内脏过敏
DOI：
10.1111/cns.13827
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发表时间：
2022-06
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
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作者：
内脏高敏感性是肠易激综合征(IBS)患者的主要临床症状。前扣带回皮质参与痛觉信息的处理。G蛋白偶联受体激酶6(GRK6)和P2Y嘌呤受体6(P2Y6)都与神经炎症和病理性疼痛有关。本研究旨在探讨GRK6和P2Y6在孕期母体应激(PMS)成年子代大鼠内脏高敏感性形成过程中的相互作用。内脏高敏感度通过腹部对结直肠扩张(CRD)的缩腹反射阈值来量化。用免疫印迹、定量聚合酶链式反应和荧光免疫组织化学方法检测GRK6和P2Y6的表达和细胞分布。免疫共沉淀法检测GRK6与P2Y6之间的相互作用。PMS大鼠ACC中GRK6的mRNA和蛋白水平均显著降低。注射GRK6高表达病毒可明显减轻经前综合征大鼠的内脏超敏反应。PMS大鼠P2Y6‘S基因表达水平、蛋白水平及膜蛋白/总蛋白比值均显著升高。微量注射P2Y6拮抗剂MRS2578可逆转经前综合征大鼠内脏超敏反应。GRK6过表达显著降低了膜蛋白中P2Y6‘S的表达和膜蛋白中P2Y6’S的比例。这些结果表明，GRK6的减少导致了PMS大鼠内脏高敏感性的发生，导致了神经细胞膜上P2Y6的积聚。目前的研究表明，PMS降低了GRK6在前扣带回的表达，进而导致GRK6在神经元细胞膜上的表达增强，从而导致PMS后代的内脏疼痛。我们的研究结果表明，GRK6/P2Y6信号通路可能是治疗内脏痛的一种有前途的策略。
Visceral hypersensitivity is a major clinic symptom in patients with irritable bowel syndrome (IBS). Anterior cingulate cortex (ACC) is involved in processing the information of pain. Both G protein‐coupled receptor kinase 6 (GRK6) and P2Y purinoceptor 6 (P2Y6) are associated with neuroinflammation and pathological pain. The aim of this study was to investigate the interaction between GRK6 and P2Y6 in ACC in the development of visceral hypersensitivity of adult offspring rats with prenatal maternal stress (PMS). Visceral hypersensitivity was quantified by abdominal withdrawal reflex threshold to colorectal distension (CRD). The expression and cellular distribution of GRK6 and P2Y6 were determined by Western blotting, qPCR, and fluorescence immunohistochemistry. Co‐immunoprecipitation was used to evaluate the interaction between GRK6 and P2Y6. The mRNA and protein levels of GRK6 were significantly decreased in ACC of PMS rats. The injection of GRK6 overexpression virus significantly attenuated visceral hypersensitivity of PMS rats. P2Y6’s mRNA level, protein level, and ratio of membrane protein over total protein expression was markedly increased in PMS rats. P2Y6 antagonist MRS2578 microinjection reversed visceral hypersensitivity of PMS rats. GRK6 overexpression significantly reduced P2Y6’s expression in membrane proteins and P2Y6’s ratio of membrane protein over total protein expression. These results indicate that decreased GRK6 leads to the accumulation of P2Y6 at neuron membrane in ACC, thereby contributing to visceral hypersensitivity of PMS rats. The present study has shown that PMS reduced GRK6 expression in the anterior cingulate cortex, and then decreased GRK6 led to an enhanced expression of P2Y6 in the neuronal cell membrane, thus eventually contributing to visceral pain of PMS offspring. Our findings suggest that the GRK6/P2Y6 signal pathway might be a promising strategy to treat visceral pain.
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影响因子：
3.7
作者：
Jagielski, Christina H.;Riehl, Megan E.
通讯作者：
Riehl, Megan E.
影响因子：
4.4
作者：
Kim, Beomsue;Jeong, Hey-kyeong;Joe, Eun-hye
通讯作者：
Joe, Eun-hye
影响因子：
2.9
作者：
Menard, L;Ferguson, SSG;Caron, MG
通讯作者：
Caron, MG
大鼠体内葡萄糖-6-磷酸脱氢酶的下调通过上调 Toll 样受体 4 导致糖尿病神经性疼痛
影响因子：
3.3
作者：
Sun, Qian;Zhang, Bing-Yu;Xu, Guang-Yin
通讯作者：
Xu, Guang-Yin
DOI：
10.1007/978-3-319-94593-4_8
发表时间：
2018-01-01
期刊：
SYSTEMS NEUROSCIENCE
影响因子：
--
作者：
Li, Ying
通讯作者：
Li, Ying