The σ-1 Receptor Interacts Directly with GluN1 But Not GluN2A in the GluN1/GluN2A NMDA Receptor
The σ-1 Receptor Interacts Directly with GluN1 But Not GluN2A in the GluN1/GluN2A NMDA Receptor
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DOI：
10.1523/jneurosci.3360-13.2013
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发表时间：
2013-11-13
影响因子：
5.3
通讯作者：
Edwardson, J. Michael
中科院分区：
文献类型：
--
作者：
Balasuriya, Dilshan;Stewart, Andrew P.;Edwardson, J. Michael
sigma-1 受体 (Sig1R) 在中枢神经系统中广泛表达，在缺血和中风以及精神分裂症中具有神经保护作用。 Sig1R 与多种离子通道发生功能性相互作用，包括 NMDA 受体 (NMDAR)。在这里，我们使用原子力显微镜 (AFM) 成像来研究 Sig1R 和 NMDAR 之间的相互作用。 Sig1R 直接与 GluN1/GluN2A NMDAR 异四聚体结合。此外，结合的 Sig1R 对之间的平均角度为 72 度。这一结果表明 Sig1R 与 GluN1 或 GluN2A 相互作用，但不能与两者相互作用，并支持我们最近的演示，即 NMDAR 亚基采用相邻（即 1/1/2/2）排列。 Sig1R 可以与 GluN1 共分离，但不能与 GluN2A 共分离，表明 GluN1 是其在 NMDAR 内的特定靶标。与此结论一致，共分离的 Sig1R 和 GluN1 的 AFM 成像显示用 Sig1R 修饰的 GluN1 二聚体。原位邻近连接测定表明，Sig1R 在完整细胞内与 GluN1（但不与 GluN2A）相互作用，并且其 C 末端位于细胞外。我们得出结论，Sig1R 通过 GluN1 亚基特异性结合 GluN1/GluN2A NMDAR。这种相互作用可能至少解释了 Sig1R 配体对 NMDAR 的部分调节作用。
The sigma-1 receptor (Sig1R) is widely expressed in the CNS, where it has a neuroprotective role in ischemia and stroke and an involvement in schizophrenia. The Sig1R interacts functionally with a variety of ion channels, including the NMDA receptor (NMDAR). Here, we used atomic force microscopy (AFM) imaging to investigate the interaction between the Sig1R and the NMDAR. The Sig1R bound directly to GluN1/GluN2A NMDAR heterotetramers. Furthermore, the mean angle between pairs of bound Sig1Rs was 72 degrees. This result suggested that the Sig1R interacts with either GluN1 or GluN2A, but not both, and supports our recent demonstration that the NMDAR subunits adopt an adjacent (i.e., 1/1/2/2) arrangement. The Sig1R could be coisolated with GluN1 but not with GluN2A, indicating that GluN1 is its specific target within the NMDAR. Consistent with this conclusion, AFM imaging of coisolated Sig1R and GluN1 revealed GluN1 dimers decorated with Sig1Rs. In situ proximity ligation assays demonstrated that the Sig1R interacts with GluN1 (but not with GluN2A) within intact cells and also that its C terminus is extracellular. We conclude that the Sig1R binds to the GluN1/GluN2A NMDAR specifically via the GluN1 subunit. This interaction likely accounts for at least some of the modulatory effects of Sig1R ligands on the NMDAR.