Delta receptors (GluD1 and GluD2), members of the large ionotropic glutamate receptor (iGluR) family, play a central role in numerous neurodevelopmental and psychiatric disorders. The amino-terminal domain (ATD) of GluD orchestrates synapse formation and maturation processes through its interaction with the Cbln family of synaptic organizers and neurexin (Nrxn). The transsynaptic triad of Nrxn–Cbln–GluD also serves as a potent regulator of synaptic plasticity, at both excitatory and inhibitory synapses. Despite these recognized functions, there is still debate as to whether GluD functions as a "canonical" ion channel, similar to other iGluRs. A recent report proposes that the ATD of GluD2 imposes conformational constraints on channel activity; removal of this constraint by binding to Cbln1 and Nrxn, or removal of the ATD, reveals channel activity in GluD2 upon administration of glycine (Gly) and d -serine ( d -Ser), two GluD ligands. We were able to reproduce currents when Gly or d -Ser was administered to clusters of heterologous human embryonic kidney 293 (HEK293) cells expressing Cbln1, GluD2 (or GluD1), and Nrxn. However, Gly or d -Ser, but also l -glutamate ( l -Glu), evoked similar currents in naive (i.e., untransfected) HEK293 cells and in GluD2-null Purkinje neurons. Furthermore, no current was detected in isolated HEK293 cells expressing GluD2 lacking the ATD upon administration of Gly. Taken together, these results cast doubt on the previously proposed hypothesis that extracellular ligands directly gate wild-type GluD channels.

中文翻译：

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缺乏 GluD 受体直接配体门控离子通道活性的证据


Delta 受体（GluD1 和 GluD2）是大离子型谷氨酸受体 (iGluR) 家族的成员，在许多神经发育和精神疾病中发挥着核心作用。 GluD 的氨基末端结构域 (ATD) 通过与突触组织者 Cbln 家族和神经毒素 (Nrxn) 的相互作用来协调突触形成和成熟过程。 Nrxn-Cbln-GluD 跨突触三联体也可作为突触可塑性的有效调节剂，无论是兴奋性突触还是抑制性突触。尽管有这些公认的功能，但关于 GluD 是否具有与其他 iGluR 类似的“规范”离子通道功能仍存在争议。最近的一份报告提出，GluD2 的 ATD 对通道活动施加构象限制；通过结合 Cbln1 和 Nrxn 或去除 ATD 来消除这种限制，揭示了给予甘氨酸 (Gly) 和 GluD2 后 GluD2 中的通道活性d -丝氨酸（ d -Ser)，两个 GluD 配体。当 Gly 或d -Ser 被给予表达 Cbln1、GluD2（或 GluD1）和 Nrxn 的异源人胚胎肾 293 (HEK293) 细胞簇。然而，甘氨酸或d -Ser，还有我-谷氨酸（我-Glu)，在初始（即未转染）HEK293 细胞和 GluD2 缺失的浦肯野神经元中引起相似的电流。此外，在给予Gly后，在表达缺乏ATD的GluD2的分离的HEK293细胞中没有检测到电流。综上所述，这些结果对之前提出的细胞外配体直接门控野生型 GluD 通道的假设产生了怀疑。