Allosteric modulation of GluN1/GluN3 NMDA receptors by GluN1-selective competitive antagonists.
Allosteric modulation of GluN1/GluN3 NMDA receptors by GluN1-selective competitive antagonists.
复制标题
DOI：
10.1085/jgp.202313340
复制
发表时间：
2023-06-05
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
与GluN1/GluN2 NMDA受体相比，GluN1/GluN3受体表现出不同寻常的激活特性。本研究探讨了GluN1选择性拮抗剂增强GluN1/GluN3反应的机制，并表明拮抗剂结合促进GluN1激动剂结合结构域构象的变化不同地调节了GluN3亚基上激动剂的效力和功效。nmda型嗜离子性谷氨酸受体对正常脑功能至关重要，并与中枢神经系统疾病有关。与GluN1和GluN2亚基组成的NMDA受体相比，GluN1和GluN3亚基组成的NMDA受体的结构和功能了解较少。GluN1/3受体表现出不同寻常的激活特性，其中甘氨酸与GluN1结合会引起强烈的脱敏，而甘氨酸单独与GluN3结合足以激活。在这里，我们探索GluN1选择性竞争拮抗剂CGP-78608和L-689,560通过阻止甘氨酸与GluN1结合来增强GluN1/ 3a和GluN1/ 3b受体的机制。我们发现CGP-78608和L-689,560都能阻止GluN1/3受体的脱敏，但与L-689,560结合的受体相比，CGP-78608结合的受体在GluN3亚基上表现出更高的甘氨酸效力和功效。此外，我们证明L-689,560是GluN1FA+TL/3A受体的有效拮抗剂，该受体突变使甘氨酸与GluN1的结合消失，并且这种抑制是通过非竞争性机制介导的，该机制涉及与突变的GluN1激动剂结合域（ABD）结合，从而负向调节GluN3A的甘氨酸效价。分子动力学模拟表明，ggp -78608和L-689,560结合或GluN1甘氨酸结合位点突变可促进GluN1 ABD的不同构象，这表明GluN1 ABD构象影响GluN3亚基的激动剂效力和功效。这些结果揭示了在CGP-78608而非L-689,560存在的情况下，甘氨酸激活天然GluN1/3A受体的机制，并证明了GluN1/3受体中强大的亚基内变构相互作用可能与脑功能和疾病中的神经元信号传导有关。
GluN1/GluN3 receptors display unusual activation properties compared to GluN1/GluN2 NMDA receptors. This study investigates mechanisms by which GluN1-selective antagonists potentiate GluN1/GluN3 responses and shows that variation in GluN1 agonist binding domain conformations promoted by antagonist binding differently modulates agonist potency and efficacy at GluN3 subunits. NMDA-type ionotropic glutamate receptors are critical for normal brain function and are implicated in central nervous system disorders. Structure and function of NMDA receptors composed of GluN1 and GluN3 subunits are less understood compared to those composed of GluN1 and GluN2 subunits. GluN1/3 receptors display unusual activation properties in which binding of glycine to GluN1 elicits strong desensitization, while glycine binding to GluN3 alone is sufficient for activation. Here, we explore mechanisms by which GluN1-selective competitive antagonists, CGP-78608 and L-689,560, potentiate GluN1/3A and GluN1/3B receptors by preventing glycine binding to GluN1. We show that both CGP-78608 and L-689,560 prevent desensitization of GluN1/3 receptors, but CGP-78608-bound receptors display higher glycine potency and efficacy at GluN3 subunits compared to L-689,560-bound receptors. Furthermore, we demonstrate that L-689,560 is a potent antagonist of GluN1FA+TL/3A receptors, which are mutated to abolish glycine binding to GluN1, and that this inhibition is mediated by a non-competitive mechanism involving binding to the mutated GluN1 agonist binding domain (ABD) to negatively modulate glycine potency at GluN3A. Molecular dynamics simulations reveal that CGP-78608 and L-689,560 binding or mutations in the GluN1 glycine binding site promote distinct conformations of the GluN1 ABD, suggesting that the GluN1 ABD conformation influences agonist potency and efficacy at GluN3 subunits. These results uncover the mechanism that enables activation of native GluN1/3A receptors by application of glycine in the presence of CGP-78608, but not L-689,560, and demonstrate strong intra-subunit allosteric interactions in GluN1/3 receptors that may be relevant to neuronal signaling in brain function and disease.
登录
查看更多内容
影响因子：
16.6
作者：
Grand T;Abi Gerges S;David M;Diana MA;Paoletti P
通讯作者：
Paoletti P
影响因子：
16.2
作者：
Bossi, Simon;Dhanasobhon, Dhanasak;Ellis-Davies, Graham C. R.;Frontera, Jimena;Van Velze, Marcel de Brito;Lourenco, Joana;Murillo, Alvaro;Lujan, Rafael;Casado, Mariano;Perez-Otano, Isabel;Bacci, Alberto;Popa, Daniela;Paoletti, Pierre;Rebola, Nelson
通讯作者：
Rebola, Nelson
影响因子：
4.6
作者：
Cummings KA;Popescu GK
通讯作者：
Popescu GK
影响因子：
4.8
作者：
Madry C;Betz H;Geiger JR;Laube B
通讯作者：
Laube B
影响因子：
4.4
作者：
FELLER, SE;ZHANG, YH;BROOKS, BR
通讯作者：
BROOKS, BR