Activation of protein kinase C is required for AMPA receptor GluR1 phosphorylation at serine 845 in the dorsal striatum following repeated cocaine administration
Activation of protein kinase C is required for AMPA receptor GluR1 phosphorylation at serine 845 in the dorsal striatum following repeated cocaine administration
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DOI：
10.1007/s00213-013-2968-1
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发表时间：
2013-06-01
影响因子：
3.4
通讯作者：
Choe, Eun Sang
中科院分区：
文献类型：
--
作者：
Oh, Jeong Hwan;Yang, Ju Hwan;Choe, Eun Sang
α -氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）受体磷酸化在药物滥用相关的AMPA受体可塑性调控中起着至关重要的作用。众所周知，AMPA受体GluR1丝氨酸845亚基（S845）的磷酸化受纹状体下游多巴胺D1受体的蛋白激酶A调控。本研究旨在通过谷氨酸受体相关和Ca2+依赖性蛋白激酶的信号机制，确定大鼠背纹状体中GluR1-S845的磷酸化是否会因重复使用可卡因而改变。全身给药可卡因（20 mg/kg，每天1次，连续7天）上调GluR1-S845磷酸化。这种上调是通过刺激I组代谢性谷氨酸受体1、n -甲基-d-天冬氨酸受体和肌醇1,4,5-三磷酸敏感受体的机制介导的。多种蛋白激酶的相互作用，包括蛋白激酶C、Ca2+/钙调素依赖性蛋白激酶II和细胞外信号调节激酶，也参与了这一事件。蛋白磷酸酶通过去磷酸化S845和磷酸化的蛋白激酶进一步控制S845的磷酸化。这些发现表明，在背纹状体中，反复服用可卡因后，谷氨酸受体偶联Ca2+依赖性蛋白激酶的相互作用上调了GluR1-S845位点AMPA受体的磷酸化。
Phosphorylation in the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors plays a crucial role in the regulation of AMPA receptor plasticity associated with drugs of abuse.It is well known that phosphorylation of AMPA receptor GluR1 subunit at serine 845 (S845) is regulated by protein kinase A downstream to dopamine D1 receptors in the striatum. This study was performed to determine whether GluR1-S845 phosphorylation in the rat dorsal striatum is altered by repeated cocaine via a signaling mechanism involving glutamate receptor-associated and Ca2+-dependent protein kinases.Systemic administration of cocaine (20 mg/kg, once a day for 7 days) upregulated GluR1-S845 phosphorylation. This upregulation was mediated via a mechanism involving stimulation of group I metabotropic glutamate receptor 1, N-methyl-d-aspartate receptors, and inositol 1,4,5-triphosphate-sensitive receptors. Interactions of several protein kinases, including protein kinase C, Ca2+/calmodulin-dependent protein kinase II, and extracellular signal-regulated kinases, are also involved in this event. Protein phosphatases further control S845 phosphorylation by dephosphorylating S845 and phosphorylated protein kinases.These findings suggest that phosphorylation of AMPA receptors at GluR1-S845 is upregulated by interactions of glutamate receptor-coupled Ca2+-dependent protein kinases following repeated cocaine administration in the dorsal striatum.