SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor dependent synaptic AMPA receptor potentiation
SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor dependent synaptic AMPA receptor potentiation
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DOI：
10.1016/j.neuron.2004.08.003
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发表时间：
2004-08-19
期刊：
影响因子：
16.2
通讯作者：
Clapham, DE
中科院分区：
文献类型：
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作者：
Krapivinsky, G;Medina, I;Clapham, DE
突触包含密集的局部化和相互作用的蛋白质，使其能够适应不断变化的输入。我们描述了一个钙敏感的蛋白复合物参与AMPA受体突触可塑性的调节。该复合物由MUPPI（一种含有多个PDZ结构域的蛋白）、SynGAP（一种突触GTP酶激活蛋白）和Ca 2 +/钙调蛋白依赖性激酶CaMKII组成。在海马神经元的突触中，SynGAP和CaMKII通过与MUPP 1的PDZ结构域的直接物理相互作用而聚集在一起，并且在该复合物中，SynGAP被磷酸化。Ca 2 +/CaM与CaMKII的结合使其与MUPPI复合物解离，并且Ca 2+通过NMDAR进入驱动SynGAP的去磷酸化。特异性肽诱导的SynGAP从MUPP 1-CaMKII复合物中解离导致SynGAP去磷酸化，伴随P38 MAPK失活、突触AMPA反应增强以及海马神经元突触中含AMPAR簇的数量增加。siRNA介导的SynGAP敲除证实了这些结果。这些数据表明SynGAP参与了NMDAR和CaMKII依赖的AMPAR运输调控。
The synapse contains densely localized and interacting proteins that enable it to adapt to changing inputs. We describe a Ca2+-sensitive protein complex involved in the regulation of AMPA receptor synaptic plasticity. The complex is comprised of MUPPI, a multi-PDZ domain-containing protein; SynGAP, a synaptic GTPase-activating protein; and the Ca2+/calmodulin-dependent kinase CaMKII. In synapses of hippocampal neurons, SynGAP and CaMKII are brought together by direct physical interaction with the PDZ domains of MUPP1, and in this complex, SynGAP is phosphorylated. Ca2+/CaM binding to CaMKII dissociates it from the MUPPI complex, and Ca2+ entering via the NMDAR drives the dephosphorylation of SynGAP. Specific peptide-induced SynGAP dissociation from the MUPP1-CaMKII complex results in SynGAP dephosphorylation accompanied by P38 MAPK inactivation, potentiation of synaptic AMPA responses, and an increase in the number of AMPAR-containing clusters in hippocampal neuron synapses. siRNA-mediated SynGAP knockdown confirmed these results. These data implicate SynGAP in NMDAR- and CaMKII-dependent regulation of AMPAR trafficking.