Calcium/Calmodulin-Dependent Protein Kinase II Mediates Group I Metabotropic Glutamate Receptor-Dependent Protein Synthesis and Long-Term Depression in Rat Hippocampus
Calcium/Calmodulin-Dependent Protein Kinase II Mediates Group I Metabotropic Glutamate Receptor-Dependent Protein Synthesis and Long-Term Depression in Rat Hippocampus
复制标题
DOI：
10.1523/jneurosci.6656-10.2011
复制
发表时间：
2011-05-18
影响因子：
5.3
通讯作者：
Abraham, Wickliffe C.
中科院分区：
文献类型：
--
作者：
Mockett, Bruce G.;Guevremont, Diane;Abraham, Wickliffe C.
大鼠海马中I组代谢型谷氨酸受体（mGluRs）的激活诱导了一种依赖于蛋白质合成的长期抑郁（LTD）形式。然而，导致启动蛋白质合成和表达的LTD后mGluR激活的细胞内机制只有部分理解。我们研究了与mGluR激活、翻译起始和诱导LTD相关的几种途径的作用。我们发现，由激动剂（RS）-3，5-二氢苯甘氨酸（DHPG）或成对脉冲突触刺激诱导的I组mGluR依赖性蛋白质合成和相关LTD依赖于钙/钙调蛋白依赖性蛋白激酶II α（CaMKII）的激活。DHPG诱导从整个海马和CA 1 minislices制备的突触神经元中磷酸化CaMKII（磷酸化CaMKII（T286））的水平的瞬时增加。在突触神经体中，DHPG还诱导eIF 4 E磷酸化增加，以及蛋白质合成增加，这被翻译抑制剂和CaMKII抑制剂1-[N，O-双（5-异喹啉磺酰基）-N-甲基-L-酪氨酰基]-4-苯基哌嗪（KN 62）和2-[N-（2-羟乙基）]N-（4-甲氧基苯磺酰基）氨基-N-（4-氯-肉桂基）-N-甲基苄胺（KN 93）消除。在现场录音从CA 1，翻译抑制剂放线菌酮和KN 62显着减少DHPG诱导的LTD。联合应用没有进一步减少LTD，这表明一个共同的机制。在全细胞记录中，第三种CaMKII抑制剂AIP（autocamtide-2-related inhibitory peptide，autocamtide-2-related inhibitory peptide）显著降低了DHPG诱导的突触电流LTD。通过阻断PKC（蛋白激酶C）或PLC（磷脂酶C）介导许多I组mGluR效应的经典途径的抑制并不损害DHPG诱导的蛋白质合成或LTD。总的来说，这些研究结果表明CaMKII在介导蛋白质合成的启动中起重要作用，然后支持DHPG诱导的LTD的突触后表达。
Activation of Group I metabotropic glutamate receptors (mGluRs) in rat hippocampus induces a form of long-term depression (LTD) that is dependent on protein synthesis. However, the intracellular mechanisms leading to the initiation of protein synthesis and expression of LTD after mGluR activation are only partially understood. We investigated the role of several pathways linked to mGluR activation, translation initiation, and induction of LTD. We found that Group I mGluR-dependent protein synthesis and associated LTD, as induced by the agonist (RS)-3,5-dihydrophenylglycine (DHPG) or paired-pulse synaptic stimulation, was dependent on activation of calcium/calmodulin-dependent protein kinase II alpha (CaMKII). DHPG induced a transient increase in the level of phospho-CaMKII (phosphoCaMKII(T286)) in synaptoneurosomes prepared from whole hippocampus and in CA1 minislices. In synaptoneurosomes, DHPG also induced an increase in phosphorylation of eIF4E, and an increase in protein synthesis that was abolished by translation inhibitors and the CaMKII inhibitors 1-[N,O-bis(5-isoquinolinesulphonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (KN62) and 2-[N-(2-hydroxyethyl)]N-(4-methoxybenzenesulfonyl)amino-N-(4-chloro-cinnamyl)-N-methylbenzylamine (KN93). In field recordings from CA1, both the translation inhibitor cycloheximide and KN62 significantly reduced DHPG-induced LTD. Combined application did not further reduce the LTD, suggesting a common mechanism. In whole-cell recordings, a third CaMKII inhibitor, AIP (autocamtide-2-related inhibitory peptide), significantly reduced the DHPG-induced LTD of synaptic currents. Inhibition of the classical pathway mediating many Group I mGluR effects by blocking PKC (protein kinase C) or PLC (phospholipase C) did not impair DHPG-induced protein synthesis or LTD. Collectively, these findings demonstrate an important role for CaMKII in mediating the initiation of protein synthesis that then supports the postsynaptic expression of DHPG-induced LTD.