Mechanisms underlying the synaptic trafficking of the glutamate delta receptor GluD1.
Mechanisms underlying the synaptic trafficking of the glutamate delta receptor GluD1.
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DOI：
10.1038/s41380-019-0378-4
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发表时间：
2019-10
影响因子：
11
通讯作者：
Nicoll, Roger A.
中科院分区：
文献类型：
--
作者：
Tao, Wucheng;Ma, Chenxue;Bemben, Michael A.;Li, Kathy H.;Burlingame, Alma L.;Zhang, Mingjie;Nicoll, Roger A.
离子型谷氨酸δ受体不结合谷氨酸，也不产生离子电流，导致难以研究这些受体的功能和运输。在这里，我们利用嵌合结构，其中GluD 1的配体结合结构域被取代的GluK 1，研究其突触贩运和可塑性。GluD 1被运输到突触，但不能表达长时程增强（LTP）。GluD 1的C-末端结构域（CT）具有经典的PDZ结合基序，这对于其他谷氨酸受体的突触运输是至关重要的，但是我们发现其与PSD-95的结合非常弱，并且删除PDZ结合基序未能改变突触运输。然而，删除整个CT取消突触贩运，但不是表面表达。我们发现苏氨酸（T）T923突变为丙氨酸破坏了突触运输。因此，与AMPAR相比，GluD 1受体具有显著不同的运输机制。这些结果突出了在单一类型的突触离子型谷氨酸受体运输规则的多样性。由于这种受体与精神分裂症有遗传相关性，我们的发现可能为理解精神分裂症提供重要线索。
Ionotropic glutamate delta receptors do not bind glutamate and do not generate ionic current, resulting in difficulty in studying the function and trafficking of these receptors. Here, we utilize chimeric constructs, in which the ligand-binding domain of GluD1 is replaced by that of GluK1, to examine its synaptic trafficking and plasticity. GluD1 trafficked to the synapse, but was incapable of expressing long-term potentiation (LTP). The C-terminal domain (CT) of GluD1 has a classic PDZ-binding motif, which is critical for the synaptic trafficking of other glutamate receptors, but we found that its binding to PSD-95 was very weak, and deleting the PDZ-binding motif failed to alter synaptic trafficking. However, deletion of the entire CT abolished synaptic trafficking, but not surface expression. We found that mutation of threonine (T) T923 to an alanine disrupted synaptic trafficking. Therefore, GluD1 receptors have strikingly different trafficking mechanisms compared with AMPARs. These results highlight the diversity of ionotropic glutamate receptor trafficking rules at a single type of synapse. Since this receptor is genetically associated with schizophrenia, our findings may provide an important clue to understand schizophrenia.
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