Ionotropic glutamate delta receptors 1 (GluD1) and 2 (GluD2) exhibit the molecular architecture of postsynaptic ionotropic glutamate receptors, but assemble into trans-synaptic adhesion complexes by binding to secreted cerebellins that in turn interact with presynaptic neurexins^1,2,3,4. It is unclear whether neurexin–cerebellin–GluD1/2 assemblies serve an adhesive synapse-formation function or mediate trans-synaptic signalling. Here we show in hippocampal synapses, that binding of presynaptic neurexin–cerebellin complexes to postsynaptic GluD1 controls glutamate receptor activity without affecting synapse numbers. Specifically, neurexin-1–cerebellin-2 and neurexin-3–cerebellin-2 complexes differentially regulate NMDA (N-methyl-d-aspartate) receptors and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors by activating distinct postsynaptic GluD1 effector signals. Of note, minimal GluD1 and GluD2 constructs containing only their N-terminal cerebellin-binding and C-terminal cytoplasmic domains, joined by an unrelated transmembrane region, fully control the levels of NMDA and AMPA receptors. The distinct signalling specificity of presynaptic neurexin-1 and neurexin-3^5,6 is encoded by their alternatively spliced splice site 4 sequences, whereas the regulatory functions of postsynaptic GluD1 are mediated by conserved cytoplasmic sequence motifs spanning 5–13 residues. Thus, GluDs are signalling molecules that regulate NMDA and AMPA receptors by an unexpected transduction mechanism that bypasses their ionotropic receptor architecture and directly converts extracellular neurexin–cerebellin signals into postsynaptic receptor responses.

离子型谷氨酸受体 1 (GluD1) 和 2 (GluD2) 表现出突触后离子型谷氨酸受体的分子结构，但通过与分泌的小脑结合而组装成跨突触粘附复合物，这些小脑又与突触前神经突相互作用^1,2,3,4 . 尚不清楚 neurexin-cerebellin-GluD1/2 组件是否具有粘附性突触形成功能或介导跨突触信号传导。在这里，我们在海马突触中显示，突触前神经突 - 小脑蛋白复合物与突触后 GluD1 的结合控制谷氨酸受体活性而不影响突触数量。具体来说，neurexin-1-cerebellin-2 和 neurexin-3-cerebellin-2 复合物差异调节 NMDA（N-甲基-d-天冬氨酸）受体和 AMPA（α-氨基-3-羟基-5-甲基-4-异恶唑丙酸）受体通过激活不同的突触后 GluD1 效应信号。值得注意的是，最小的 GluD1 和 GluD2 构建体仅包含它们的 N 端小脑结合和 C 端细胞质结构域，由不相关的跨膜区域连接，完全控制 NMDA 和 AMPA 受体的水平。突触前 neurexin-1 和 neurexin-3 的不同信号特异性^5,6由它们交替剪接的剪接位点 4 序列编码，而突触后 GluD1 的调节功能由跨越 5-13 个残基的保守细胞质序列基序介导。因此，GluD 是一种信号分子，通过一种意想不到的转导机制来调节 NMDA 和 AMPA 受体，这种转导机制绕过它们的离子型受体结构，直接将细胞外神经突蛋白-小脑蛋白信号转化为突触后受体反应。