ERK1/2 but not p38 MAP kinase is essential for the long-term depression in mouse cerebellar slices
ERK1/2 but not p38 MAP kinase is essential for the long-term depression in mouse cerebellar slices
复制标题
DOI：
10.1111/j.1460-9568.2006.05055.x
复制
发表时间：
2006-09-01
影响因子：
3.4
通讯作者：
Yuzaki, Michisuke
中科院分区：
文献类型：
--
作者：
Ito-Ishida, Aya;Kakegawa, Wataru;Yuzaki, Michisuke
丝裂原活化蛋白激酶（MAPK）级联对突触可塑性和学习至关重要。在海马中，三个不同的MAPK亚家族，细胞外信号调节激酶1/2 （ERK1/2）、p38 MAPK和c-Jun nh2末端蛋白激酶（JNK），分别在长期增强（LTP）、长期抑制（LTD）和LTP后去增强过程中选择性地调节活性依赖性谷氨酸受体的转运。虽然小脑平行纤维-浦肯野细胞突触的LTP和LTD被认为是由谷氨酸受体运输控制的，但MAPK亚家族的参与尚未在小脑切片制备中得到系统的研究。为了阐明MAPK级联在小脑LTD中的作用，我们使用ICR小鼠小脑切片进行了生化和电生理分析。利用MAPKs磷酸化特异性抗体进行免疫印迹分析发现，在这3种MAPKs中，ERK1/2被phorbol酯特异性激活，可在小脑切片中诱导LTD。此外，MAPK激酶- erk1 /2通路的特异性抑制剂U0126在小脑切片中消除了LTD的诱导作用，而p38 MAPK和JNK的特异性抑制剂SB203580和SP600125则没有作用。虽然代谢型谷氨酸受体1 （mGluR1）已被认为是ERK1/2在细胞培养制剂中可能的下游靶点，但U0126在片中对mGluR1激活的慢兴奋性突触后电流（EPSCs）没有影响。这些发现表明，与p38 MAPK介导的海马LTD不同，小脑LTD期间谷氨酸受体的转运受到与ERK1/2相关的独特机制的调节。
Mitogen-activated protein kinase (MAPK) cascade is essential for synaptic plasticity and learning. In the hippocampus, three different MAPK subfamilies, extracellular signal-regulated kinase 1/2 (ERK1/2), p38 MAPK and c-Jun NH2-terminal protein kinase (JNK), selectively regulate activity-dependent glutamate receptor trafficking during long-term potentiation (LTP), long-term depression (LTD), and depotentiation after LTP, respectively. Although LTP and LTD at cerebellar parallel fibre (PF)-Purkinje cell synapses are thought to be controlled by glutamate receptor trafficking, the involvement of MAPK subfamilies has not been systemically studied in cerebellar slice preparations. To clarify the role of the MAPK cascade in cerebellar LTD, we performed biochemical and electrophysiological analyses using ICR mouse cerebellar slices. Immunoblot analyses using phosphorylation-specific antibodies for MAPKs revealed that among the three MAPKs, ERK1/2 was specifically activated by phorbol ester, which could induce LTD in cerebellar slices. In addition, U0126, a specific inhibitor of the MAPK kinase-ERK1/2 pathway, abrogated the induction of LTD in cerebellar slices, whereas SB203580 and SP600125, specific inhibitors of p38 MAPK and JNK, respectively, had no effect. Although metabotropic glutamate receptor 1 (mGluR1) has been suggested as a possible downstream target of ERK1/2 in cell-culture preparations, mGluR1-activated slow excitatory postsynaptic currents (EPSCs) were not affected by U0126 treatment in slices. These findings indicate that unlike hippocampal LTD mediated by p38 MAPK, glutamate receptor trafficking during cerebellar LTD was regulated by a distinct mechanism involving ERK1/2 in slice preparations.