Latrophilin GPCR signaling mediates synapse formation.
Latrophilin GPCR signaling mediates synapse formation.
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嗜Latrophilin GPCR信号传导介导突触形成。
DOI：
10.7554/elife.65717
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发表时间：
2021-03-01
期刊：
影响因子：
7.7
通讯作者：
Südhof TC
中科院分区：
文献类型：
--
作者：
Sando R;Südhof TC
大脑中的神经回路组装需要精确建立突触连接，但突触组装的机制仍不完全清楚。 Latrophilins 是突触后粘附 GPCR，与突触前 tenurins 和 FLRT 形成跨突触复合物。在小鼠 CA1 区神经元中，Latrophilin-2 和 Latrophilin-3 分别对于内嗅皮质衍生和 Schaffer 侧枝衍生突触的形成至关重要。然而，尚不清楚 latrophilins 是否在突触形成中发挥 GPCR 的作用。在这里，我们发现 Latrophilin-2 和 Latrophilin-3 表现出组成型 GPCR 活性，可增加 cAMP 水平，但这种活性被干扰 G 蛋白和 GPCR 抑制蛋白相互作用的突变所阻断。相同的突变损害了 Latrophilin-2 和 Latrophilin-3 在体内挽救 Latrophilin-2 和 Latrophilin-3 敲除神经元中突触丢失表型的能力。我们的结果表明 Latrophilin-2 和 Latrophilin-3 在突触形成过程中需要 GPCR 信号传导，这表明 Latrophilin 通过激活经典的 GPCR 信号通路促进海马突触形成。
Neural circuit assembly in the brain requires precise establishment of synaptic connections, but the mechanisms of synapse assembly remain incompletely understood. Latrophilins are postsynaptic adhesion-GPCRs that engage in trans-synaptic complexes with presynaptic teneurins and FLRTs. In mouse CA1-region neurons, Latrophilin-2 and Latrophilin-3 are essential for formation of entorhinal-cortex-derived and Schaffer-collateral-derived synapses, respectively. However, it is unknown whether latrophilins function as GPCRs in synapse formation. Here, we show that Latrophilin-2 and Latrophilin-3 exhibit constitutive GPCR activity that increases cAMP levels, which was blocked by a mutation interfering with G-protein and arrestin interactions of GPCRs. The same mutation impaired the ability of Latrophilin-2 and Latrophilin-3 to rescue the synapse-loss phenotype in Latrophilin-2 and Latrophilin-3 knockout neurons in vivo. Our results suggest that Latrophilin-2 and Latrophilin-3 require GPCR signaling in synapse formation, indicating that latrophilins promote synapse formation in the hippocampus by activating a classical GPCR-signaling pathway.