Ketamine-induced inhibition of glycogen synthase kinase-3 contributes to the augmentation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor signaling.
Ketamine-induced inhibition of glycogen synthase kinase-3 contributes to the augmentation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor signaling.
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DOI：
10.1111/bdi.12436
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发表时间：
2016-09
影响因子：
5.4
通讯作者：
Jope RS
中科院分区：
文献类型：
--
作者：
Beurel E;Grieco SF;Amadei C;Downey K;Jope RS
已发现亚麻醉剂量的氯胺酮可提供快速的抗抑郁作用，表明氯胺酮靶向的细胞信号传导系统是治疗干预的潜在位点。氯胺酮作为N-甲基-D-天冬氨酸（NMDA）受体的拮抗剂，动物研究表明，α-氨基-3-羟基-5-甲基异恶唑-4-丙酸（AMPA）受体随后增强信号传导对抗抑郁药结局至关重要。在这项研究中，我们测试了氯胺酮对糖原合成酶激酶-3（GSK 3）的抑制作用是否会影响海马细胞表面AMPA受体，方法是对野生型和GSK 3敲入小鼠的膜和突触体提取物进行免疫印迹。用抗抑郁剂量的氯胺酮治疗增加了海马膜AMPA谷氨酸受体（GluA）1亚基的水平，但没有改变GluA 2、GluA 3或GluA 4的定位。氯胺酮的这种作用在表达不能被氯胺酮抑制的突变体GSK 3的GSK 3敲入小鼠中被消除，表明氯胺酮诱导的GSK 3抑制对于细胞表面AMPA GluA 1亚基的上调是必需的。AMPA受体运输受突触后密度-95（PSD-95）（GSK 3的底物）调节。氯胺酮治疗降低了海马膜Thr-19上磷酸化PSD-95的水平，Thr-19是促进AMPA受体内化的GSK 3的靶点。这些结果表明，氯胺酮诱导的GSK 3抑制导致PSD-95磷酸化减少，减少AMPA GluA 1亚基的内化，从而允许氯胺酮治疗后通过AMPA受体增强信号传导。
Sub-anesthetic doses of ketamine have been found to provide rapid antidepressant actions, indicating that the cellular signaling systems targeted by ketamine are potential sites for therapeutic intervention. Ketamine acts as an antagonist of N-methyl-D-aspartate (NMDA) receptors, and animal studies indicate that subsequent augmentation of signaling by α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors is critical for the antidepressant outcome. In this study, we tested if the inhibitory effect of ketamine on glycogen synthase kinase-3 (GSK3) affected hippocampal cell-surface AMPA receptors using immunoblotting of membrane and synaptosomal extracts from wild-type and GSK3 knockin mice. Treatment with an antidepressant dose of ketamine increased the hippocampal membrane level of the AMPA glutamate receptor (GluA)1 subunit, but did not alter the localization of GluA2, GluA3, or GluA4. This effect of ketamine was abrogated in GSK3 knockin mice expressing mutant GSK3 that cannot be inhibited by ketamine, demonstrating that ketamine-induced inhibition of GSK3 is necessary for up-regulation of cell surface AMPA GluA1 subunits. AMPA receptor trafficking is regulated by post-synaptic density-95 (PSD-95), a substrate for GSK3. Ketamine treatment decreased the hippocampal membrane level of phosphorylated PSD-95 on Thr-19, the target of GSK3 that promotes AMPA receptor internalization. These results demonstrate that ketamine-induced inhibition of GSK3 causes reduced phosphorylation of PSD-95, diminishing the internalization of AMPA GluA1 subunits to allow for augmented signaling through AMPA receptors following ketamine treatment.
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影响因子：
64.8
作者：
Autry, Anita E.;Adachi, Megunai;Nosyreva, Elena;Na, Elisa S.;Los, Maarten F.;Cheng, Peng-fei;Kavalali, Ege T.;Monteggia, Lisa M.
通讯作者：
Monteggia, Lisa M.
DOI：
10.1126/science.1190287
发表时间：
2010-08-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Li N;Lee B;Liu RJ;Banasr M;Dwyer JM;Iwata M;Li XY;Aghajanian G;Duman RS
通讯作者：
Duman RS
影响因子：
7.6
作者：
Li, XH;Zhu, W;Jope, RS
通讯作者：
Jope, RS
影响因子：
4.2
作者：
De Sarno, P;Bijur, GN;Jope, RS
通讯作者：
Jope, RS
影响因子：
4.8
作者：
Chiu, Chi-Tso;Scheuing, Lisa;Chuang, De-Maw
通讯作者：
Chuang, De-Maw