Regionally selective activation and differential regulation of ERK, JNK and p38 MAP kinase signalling pathway by protein kinase C in mood modulation
Regionally selective activation and differential regulation of ERK, JNK and p38 MAP kinase signalling pathway by protein kinase C in mood modulation
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DOI：
10.1017/s1461145711000897
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发表时间：
2012-07-01
影响因子：
4.8
通讯作者：
Ghelardini, Carla
中科院分区：
文献类型：
--
作者：
Galeotti, Nicoletta;Ghelardini, Carla
越来越多的证据表明，细胞外信号调节激酶(ERK)通路可能参与了抑郁症的神经元调控。P38MAPK和c-Jun-N端激酶/应激激活蛋白激酶(JNK/SAPK)也属于MAPK家族，主要作为细胞应激的介体。由于越来越多的证据表明应激是抑郁症易感性的重要因素，在强迫游泳试验(FST)和尾部悬吊试验(TST)中，研究了ERK、JNK和p38MAPK信号通路在情绪调节中的作用。通过免疫印迹实验研究FST和TST单次急性给药对大鼠海马区和大脑皮层MAPK表达及磷酸化的影响。在暴露于FST和TST的动物的海马区，观察到强烈的PKC依赖的ERK1、ERK2、INK和p38MAPK的磷酸化。在额叶皮质，FST和TST引起依赖PKC的ERK2和p38MAPK磷酸化增加，非PKC依赖的JNK和cAMP反应元件结合蛋白(CREB)激活，而ERK1参与。PKC阻滞剂Calphostin C(0.05-0.1ug i.c.v.)、MEK抑制剂U0126(10-20mU g i.c.v)、p38MAPK抑制剂SB203580(5-20ug i.c.V.)和JNK抑制剂II(0.5-5微克i.c.v)，在不改变运动活性的情况下产生抗抑郁药样行为。这些结果表明，暴露在行为绝望范式下的动物的海马区和额叶皮层中MAPK的激活是不同的。急性阻断MAPK信号通路所产生的抗抑郁药样表型也被证实。
A growing body of evidence indicates that the extracellular signal-regulated kinase (ERK) pathway may participate in the neuronal modulation of depression. p38MAPK and c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK) also belong to the MAPK family which mainly function as mediators of cellular stresses. Since increasing evidence implicates stress as an important factor in vulnerability to depressive illnesses, the involvement of ERK, JNK and p38MAPK pathways in the modulation of mood was investigated in the forced swim test (FST) and tail suspension test (TST). The effect produced by a single acute session of FST and TST on hippocampal and cortical MAPK expression and phosphorylation was investigated by immunoblotting experiments. In the hippocampus of animals exposed to FST and TST, an intensive, PKC-dependent, ERK1, ERK2, INK, and p38MAPK phosphorylation was observed. In the frontal cortex, the FST and TST produced a PKC-dependent increase of ERK2 and p38MAPK phosphorylation, a PKC-independent activation of JNK and cAMP response element-binding protein (CREB) whereas any involvement of ERK1 was detected. The PKC blocker calphostin C (0.05-0.1 mu g i.c.v.), the MEK inhibitor U0126 (10-20 mu g the p38MAPK inhibitor SB203580 (5-20 mu g i.c.v.) and the JNK inhibitor II (0.5-5 mu g i.c.v.), produced antidepressant-like behaviour without altering locomotor activity. These results illustrate a differentially mediated activation of MAPK in hippocampus and frontal cortex of animals exposed to behavioural despair paradigms. An antidepressant-like phenotype produced by acute blockade of MAPK signalling was also demonstrated.