Latrophilin GPCRs direct synapse specificity by coincident binding of FLRTs and teneurins
Latrophilin GPCRs direct synapse specificity by coincident binding of FLRTs and teneurins
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DOI：
10.1126/science.aav7969
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发表时间：
2019-02-22
期刊：
影响因子：
56.9
通讯作者：
Sudhof, Thomas C.
中科院分区：
文献类型：
--
作者：
Sando, Richard;Jiang, Xian;Sudhof, Thomas C.
细胞粘附分子的双向信号被认为介导突触的形成，但涉及的机制仍然难以捉摸。我们发现，粘附G蛋白偶联受体latrophilin-2和latrophilin-3选择性直接形成的穿孔路径和Schaffer侧支突触，分别到海马CA 1区神经元。Latrophilin-3结合两个跨细胞配体：纤连蛋白富含亮氨酸重复跨膜蛋白（FLRT）和端神经素。在体内转基因小鼠中，这两种结合活性都是输入特异性突触形成所必需的，这表明这两种配体的同时结合是突触形成所必需的。在体外培养的神经元中，teneurin或FLRT单独不诱导兴奋性突触形成，而它们一起有效地这样做。因此，突触后latrophilins促进兴奋性突触的形成，同时结合两个无关的突触前配体，这是需要在特定的树突定位的突触输入的形成。
Bidirectional signaling by cell adhesion molecules is thought to mediate synapse formation, but the mechanisms involved remain elusive. We found that the adhesion G protein-coupled receptors latrophilin-2 and latrophilin-3 selectively direct formation of perforant-path and Schaffer-collateral synapses, respectively, to hippocampal CA1-region neurons. Latrophilin-3 binds to two transcellular ligands: fibronectin leucine-rich repeat transmembrane proteins (FLRTs) and teneurins. In transgenic mice in vivo, both binding activities were required for input-specific synapse formation, which suggests that coincident binding of both ligands is necessary for synapse formation. In cultured neurons in vitro, teneurin or FLRT alone did not induce excitatory synapse formation, whereas together they potently did so. Thus, postsynaptic latrophilins promote excitatory synapse formation by simultaneous binding of two unrelated presynaptic ligands, which is required for formation of synaptic inputs at specific dendritic localizations.