N-methyl-D-aspartate receptor- and metabotropic glutamate receptor-dependent long-term depression are differentially regulated by the ubiquitin-proteasome system.
N-methyl-D-aspartate receptor- and metabotropic glutamate receptor-dependent long-term depression are differentially regulated by the ubiquitin-proteasome system.
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DOI：
10.1111/j.1460-9568.2009.06950.x
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发表时间：
2009-10
期刊：
影响因子：
--
通讯作者：
Malenka RC
中科院分区：
文献类型：
--
作者：
Citri A;Soler-Llavina G;Bhattacharyya S;Malenka RC
CA1 锥体神经元的长期抑制 (LTD) 可以通过激活 NMDA 受体 (NMDAR) 或代谢型谷氨酸受体 (mGluR) 来诱导，这两种受体都通过 AMPA 受体 (AMPAR) 内吞作用引起突触功效的变化。为了阐明泛素-蛋白酶体系统在这些形式的 LTD 期间调节 AMPAR 内吞作用的作用，我们研究了蛋白酶体降解和蛋白质泛素化的药理学抑制剂对离体大鼠海马培养物中含有 GluR1 的 AMPAR 内吞作用的影响，以及急性大鼠海马中兴奋性突触反应的 LTD 作用。 切片。我们的研究结果表明，泛素蛋白酶体系统对 NMDAR 诱导与 mGluR 诱导的 AMPAR 内吞作用以及随后的 LTD 的贡献存在显着差异。 NMDAR 诱导的 AMPAR 内吞作用和 LTD 的发生独立于蛋白酶体功能，但似乎至少部分依赖于泛素化。相反，mGluR 诱导的 AMPAR 内吞作用和 LTD 通过抑制蛋白酶体降解以及通过蛋白质泛素化抑制剂而增强。此外，在抑制泛素化或蛋白酶体降解后，mGluR 诱导的膜去极化和 Erk 激活的衰减被延迟。这些结果表明，虽然 NMDAR 依赖性 LTD 可能利用泛素作为 AMPAR 内吞作用的信号，但 mGluR 诱导的信号传导和 LTD 受到涉及泛素-蛋白酶体系统的反馈机制的限制。
Long-term depression (LTD) in CA1 pyramidal neurons can be induced by activation of either NMDA receptors (NMDARs) or metabotropic glutamate receptors (mGluRs), both of which elicit changes in synaptic efficacy through AMPA receptor (AMPAR) endocytosis. To address the role of the ubiquitin-proteasome system in regulating AMPAR endocytosis during these forms of LTD, we examined the effects of pharmacological inhibitors of proteasomal degradation and protein ubiquitination on endocytosis of GluR1-containing AMPARs in dissociated rat hippocampal cultures as well as LTD of excitatory synaptic responses in acute rat hippocampal slices. Our findings suggest that the contribution of the ubiquitin-proteasome system to NMDAR-induced versus mGluR-induced AMPAR endocytosis and the consequent LTD differs significantly. NMDAR-induced AMPAR endocytosis and LTD occur independently of proteasome function, but appear to depend, at least in part, on ubiquitination. In contrast, mGluR-induced AMPAR endocytosis and LTD are enhanced by inhibition of proteasomal degradation, as well as by the inhibitor of protein ubiquitination. Furthermore, the decay of mGluR-induced membrane depolarization and Erk activation is delayed following inhibition of either ubiquitination or proteasomal degradation. These results suggest that while NMDAR-dependent LTD may utilize ubiquitin as a signal for AMPAR endocytosis, mGluR-induced signaling and LTD is limited by a feedback mechanism that involves the ubiquitin-proteasome system.
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DOI：
10.1073/pnas.89.10.4363
发表时间：
1992-05-15
影响因子：
11.1
作者：
DUDEK, SM;BEAR, MF
通讯作者：
BEAR, MF
影响因子：
16.2
作者：
Ehlers, MD
通讯作者：
Ehlers, MD
影响因子：
5.5
作者：
Dolen, Gul;Bear, Mark F.
通讯作者：
Bear, Mark F.
影响因子：
64.8
作者：
Bennett, Eric J.;Shaler, Thomas A.;Kopito, Ron R.
通讯作者：
Kopito, Ron R.
影响因子：
56.9
作者：
BOLSHAKOV, VY;SIEGELBAUM, SA
通讯作者：
SIEGELBAUM, SA