Activation of glycine site and GluN2B subunit of NMDA receptors is necessary for ERK/CREB signaling cascade in rostral anterior cingulate cortex in rats: Implications for affective pain
Activation of glycine site and GluN2B subunit of NMDA receptors is necessary for ERK/CREB signaling cascade in rostral anterior cingulate cortex in rats: Implications for affective pain
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NMDA 受体甘氨酸位点和 GluN2B 亚基的激活对于大鼠前扣带皮层 ERK/CREB 信号级联反应是必要的：对情感性疼痛的影响
DOI：
10.1007/s12264-012-1060-x
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发表时间：
2012-02-01
影响因子：
5.6
通讯作者：
Zhang, Yu-Qiu
中科院分区：
文献类型：
--
作者：
Cao, Hong;Ren, Wen-Hua;Zhang, Yu-Qiu
目的嘴前扣带回(RACC)参与处理疼痛的情绪成分。N-甲基-D-天冬氨酸受体(NMDAR)在rACC中高表达，通过激活涉及环磷酸腺苷(CAMP)/蛋白激酶A(PKA)和/或细胞外调节激酶(ERK)/cAMP反应元件结合蛋白(CREB)的信号通路来介导疼痛相关效应。本研究探讨了NMDAR甘氨酸位点和GluN2B亚基在体内外ERK和CREB活化中的作用。方法采用免疫组织化学和Western印迹方法分别检测ERK和CREB在体内外的表达。结果NMDAR拮抗剂DL-2-氨基-5-磷酸-新戊酸可抑制PERK和pCREB在rACC中的表达。选择性地阻断NMDAR GluN2B亚单位和甘氨酸结合位点，或降解甘氨酸结合位点的内源性D-丝氨酸，均显著降低rACC中PERK和pCREB表达的上调。结论NMDARs的甘氨酸位点或GluN2B亚基参与了大鼠脑片局部应用NMDA或后爪注射5%福尔马林诱导的ERK和CREB的磷酸化，这可能是痛觉发生的基本分子机制。
ObjectiveThe rostral anterior cingulate cortex (rACC) is implicated in processing the emotional component of pain. N-methyl-D-aspartate receptors (NMDARs) are highly expressed in the rACC and mediate painrelated affect by activating a signaling pathway that involves cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and/or extracellular regulated kinase (ERK)/cAMP-response element-binding protein (CREB). The present study investigated the contributions of the NMDAR glycine site and GluN2B subunit to the activation of ERK and CREB bothin vitroandin vivoin rat rACC.MethodsImmunohistochemistry and Western blot analysis were used to separately assess the expression of phospho-ERK (pERK) and phospho-CREB (pCREB)in vitroandin vivo. Double immunostaining was also used to determine the colocalization of pERK and pCREB.ResultsBoth bath application of NMDA in brain slicesin vitroand intraplantar injection of formalin into the rat hindpawin vivoinduced significant up-regulation of pERK and pCREB in the rACC, which was inhibited by the NMDAR antagonistDL-2-amino-5-phospho-novaleric acid. Selective blockade of the NMDAR GluN2B subunit and the glycinebinding site, or degradation of endogenousD-serine, a co-agonist for the glycine site, significantly decreased the up-regulation of pERK and pCREB expression in the rACC. Further, the activated ERK predominantly colocalized with CREB.ConclusionEither the glycine site or the GluN2B subunit of NMDARs participates in the phosphorylation of ERK and CREB induced by bath application of NMDA in brain slices or hindpaw injection of 5% formalin in rats, and these might be fundamental molecular mechanisms underlying pain affect.