期刊
JOURNAL OF NEUROSCIENCE
卷 30, 期 45, 页码 15304-15316出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4255-10.2010
关键词
-
资金
- National Institutes of Health [DA000564, DA011806, DA020582, K02-DA025048, K05-DA00513]
- American Health Assistance Foundation
Chronic morphine treatment resulting in the alteration of postsynaptic levels of AMPA receptors, thereby modulating synaptic strength, has been reported. However, the mechanism underlying such drug-induced synaptic modification has not been resolved. By monitoring the GluR1 trafficking in primary hippocampal neurons using the pHluorin-GluR1 imaging and biotinylation studies, we observed that prolonged morphine exposure significantly induced loss of synaptic and extrasynaptic GluR1 by internalization. The morphine-induced GluR1 endocytosis was independent of neural network activities or NMDA receptor activities, as neither blocking the sodium channels with tetrodotoxin nor NMDA receptors with DL-APV altered the effects of morphine. Instead, morphine-induced GluR1 endocytosis is attributed to a change in the phosphorylation state of the GluR1 at Ser(845) as morphine significantly decreased the dephosphorylation of GluR1 at this site. Such changes in Ser(845) phosphorylation required morphine-induced activation of calcineurin, based on the observations that a calcineurin inhibitor, FK506, completely abrogated the dephosphorylation, and morphine treatment led to an increase in calcineurin enzymatic activity, even in the presence of DL-APV. Importantly, pretreatment with FK506 and overexpression of the GluR1 mutants, S845D (phospho-mimic) or S845A (phospho-blocking) attenuated the morphine-induced GluR1 endocytosis. Therefore, the calcineurin-mediated GluR1-S845 dephosphorylation is critical for the morphine-induced changes in the postsynaptic AMPA receptor level. Together, these findings reveal a novel molecular mechanism for opioid-induced neuronal adaptation and/or synaptic impairment.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据