A single-channel mechanism for pharmacological potentiation of GluN1/GluN2A NMDA receptors.
A single-channel mechanism for pharmacological potentiation of GluN1/GluN2A NMDA receptors.
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DOI：
10.1038/s41598-017-07292-8
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发表时间：
2017-07-31
影响因子：
4.6
通讯作者：
Dravid SM
中科院分区：
文献类型：
--
作者：
Chopra DA;Sapkota K;Irvine MW;Fang G;Jane DE;Monaghan DT;Dravid SM
NMDAR参与多种神经病理过程。最近发现了新的NMDAR正变构调节剂，但它们对NMDAR门控的影响在很大程度上还不清楚。为此，我们测试了一种新开发的分子UBP684对GluN1/GluN2A受体的影响。我们发现，UBP684增强了穿孔贴片条件下观察到的全细胞电流，并减缓了受体的失活。在单通道级别，UBP684显著缩短了长关闭时间，并显著增加了平均打开时间。这些变化类似于NMDAR突变体所产生的变化，在NMDAR突变体中，配体结合域(LBD)通过加入二硫键被锁定在闭合的翻盖构象中。由于锁定的谷氨酸结合裂隙主要参与受体的作用，这些结果表明UBP684结合可能诱导类似于谷氨酸LBD锁定状态的构象转换。与这一预测一致，与仅锁定GluN1 LBD的NMDAR相比，仅锁定GluN1 LBD的NMDAR的增强作用更大。对接研究表明，UBP684与GluN1和GluN2LBD界面结合，支持其稳定LBD闭合构象的潜在能力。总之，这些研究确定了一种促进NMDARs功能的新的药理学机制。
NMDA receptors (NMDARs) contribute to several neuropathological processes. Novel positive allosteric modulators (PAMs) of NMDARs have recently been identified but their effects on NMDAR gating remain largely unknown. To this end, we tested the effect of a newly developed molecule UBP684 on GluN1/GluN2A receptors. We found that UBP684 potentiated the whole-cell currents observed under perforated-patch conditions and slowed receptor deactivation. At the single channel level, UBP684 produced a dramatic reduction in long shut times and a robust increase in mean open time. These changes were similar to those produced by NMDAR mutants in which the ligand-binding domains (LBDs) are locked in the closed clamshell conformation by incorporating a disulfide bridge. Since the locked glutamate-binding clefts primarily contributes to receptor efficacy these results suggests that UBP684 binding may induce switch in conformation similar to glutamate LBD locked state. Consistent with this prediction UBP684 displayed greater potentiation of NMDARs with only the GluN1 LBD locked compared to NMDARs with only the GluN2 LBD locked. Docking studies suggest that UBP684 binds to the GluN1 and GluN2 LBD interface supporting its potential ability in stabilizing the LBD closed conformation. Together these studies identify a novel pharmacological mechanism of facilitating the function of NMDARs.
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影响因子：
5.3
作者：
Kussius, Cassandra L.;Popescu, Gabriela K.
通讯作者：
Popescu, Gabriela K.
影响因子：
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通讯作者：
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