The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
Department of Biochemistry and Molecular Biology, Center for Membrane Biology, University of Texas Health Science Center at Houston, Houston, TX, USA.
Nat Commun. 2024 Oct 13;15(1):8841. doi: 10.1038/s41467-024-53181-w.
N-methyl-D-aspartate (NMDA) receptors are ionotropic glutamate receptors involved in learning and memory. NMDA receptors primarily comprise two GluN1 and two GluN2 subunits. The GluN2 subunit dictates biophysical receptor properties, including the extent of receptor activation and desensitization. GluN2A- and GluN2D-containing receptors represent two functional extremes. To uncover the conformational basis of their functional divergence, we utilize single-molecule fluorescence resonance energy transfer to probe the extracellular domains of these receptor subtypes under resting and ligand-bound conditions. We find that the conformational profile of the GluN2 amino-terminal domain correlates with the disparate functions of GluN2A- and GluN2D-containing receptors. Changes at the pre-transmembrane segments inversely correlate with those observed at the amino-terminal domain, confirming direct allosteric communication between these domains. Additionally, binding of a positive allosteric modulator at the transmembrane domain shifts the conformational profile of the amino-terminal domain towards the active state, revealing a bidirectional allosteric pathway between extracellular and transmembrane domains.
N-甲基-D-天冬氨酸（NMDA）受体是参与学习和记忆的离子型谷氨酸受体。NMDA 受体主要由两个 GluN1 和两个 GluN2 亚基组成。GluN2 亚基决定了受体的生物物理特性，包括受体的激活和脱敏程度。包含 GluN2A 和 GluN2D 的受体代表了两种功能极端。为了揭示它们功能分歧的构象基础，我们利用单分子荧光共振能量转移技术在静息和配体结合条件下探测这些受体亚型的细胞外结构域。我们发现，GluN2 氨基末端结构域的构象特征与包含 GluN2A 和 GluN2D 的受体的不同功能相关。跨膜片段的变化与氨基末端结构域观察到的变化相反，证实了这些结构域之间的直接变构通讯。此外，跨膜结构域上正变构调节剂的结合将氨基末端结构域的构象特征向活性状态移动，揭示了细胞外和跨膜结构域之间的双向变构途径。
