GluD1 is a signal transduction device disguised as an ionotropic receptor.
GluD1 is a signal transduction device disguised as an ionotropic receptor.
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DOI：
10.1038/s41586-021-03661-6
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发表时间：
2021-07
期刊：
影响因子：
64.8
通讯作者：
Südhof TC
中科院分区：
文献类型：
--
作者：
Dai J;Patzke C;Liakath-Ali K;Seigneur E;Südhof TC
离子型谷氨酸δ受体1（GluD 1）和2（GluD 2）表现出突触后离子型谷氨酸受体的分子结构，但通过结合分泌的小脑蛋白组装成跨突触粘附复合物，小脑蛋白又与突触前神经毒素相互作用。目前尚不清楚neurexin-cerebellin-GluD 1/2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，我们表明，在海马突触，突触前neurexin-cerebellin复合物的突触后GluD 1控制谷氨酸受体的活性，而不影响突触数量的结合。具体而言，neurexin-1-cerebellin-2和neurexin-3-cerebellin-2复合物通过激活不同的突触后GluD 1效应信号来差异调节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。值得注意的是，最小的GluD 1和GluD 2结构只包含它们的N-末端小脑蛋白结合和C-末端胞质结构域，由不相关的跨膜区连接，完全控制NMDA和AMPA受体的水平。突触前neurexin-1和neurexin-3的不同信号传导特异性由它们的选择性剪接位点4序列编码，而突触后GluD 1的调节功能由跨越5-13个残基的保守胞质序列基序介导。因此，GluDs是通过一种意想不到的转导机制调节NMDA和AMPA受体的信号分子，该机制绕过它们的离子型受体结构并直接将细胞外neurexin-cerebellin信号转化为突触后受体反应。
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. 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 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.
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