Chronic intermittent alcohol disrupts the GluN2B-associated proteome and specifically regulates group I mGlu receptor-dependent long-term depression.
Chronic intermittent alcohol disrupts the GluN2B-associated proteome and specifically regulates group I mGlu receptor-dependent long-term depression.
复制标题
慢性间歇性酒精破坏了与GluN2B相关的蛋白质组，并专门调节了MGLU受体依赖性的长期抑郁症。
DOI：
10.1111/adb.12319
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发表时间：
2017-03
影响因子：
3.4
通讯作者：
Winder DG
中科院分区：
文献类型：
--
作者：
Wills TA;Baucum AJ 2nd;Holleran KM;Chen Y;Pasek JG;Delpire E;Tabb DL;Colbran RJ;Winder DG
N-methyl-D-aspartate receptors (NMDARs) are major targets of both acute and chronic alcohol, as well as regulators of plasticity in a number of brain regions. Aberrant plasticity may contribute to the treatment resistance and high relapse rates observed in alcoholics. Recent work suggests that chronic alcohol treatment preferentially modulates both the expression and subcellular localization of NMDARs containing the GluN2B subunit. Signaling through synaptic and extrasynaptic GluN2B-NMDARs has already been implicated in the pathophysiology of various other neurological disorders. NMDARs interact with a large number of proteins at the glutamate synapse, and a better understanding of how alcohol modulates this proteome is needed. We employed a discovery-based proteomic approach in subcellular fractions of hippocampal tissue from chronic intermittent alcohol (CIE) exposed C57Bl/6j mice to gain insight into alcohol-induced changes in GluN2B signaling complexes. Protein enrichment analyses revealed changes in the association of postsynaptic proteins, including scaffolding, glutamate receptor, and PDZ-domain binding proteins with GluN2B. In particular, GluN2B interaction with metabotropic glutamate (mGlu)1/5 receptor-dependent long-term depression (LTD) associated proteins such as Arc and Homer 1 was increased, while GluA2 was decreased. Accordingly, we found a lack of mGlu1/5 induced-LTD while α1-adrenergic receptor-induced LTD remained intact in hippocampal CA1 following CIE. These data suggest that CIE specifically disrupts mGlu1/5-LTD, representing a possible connection between NMDAR and mGlu receptor signaling. These studies not only demonstrate a new way in which alcohol can modulate plasticity in the hippocampus but emphasize the utility of this discovery-based proteomic approach to generate new hypotheses regarding alcohol-related mechanisms.
