Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, 33458, USA.
Mol Psychiatry. 2019 Dec;24(12):1902-1919. doi: 10.1038/s41380-019-0512-3. Epub 2019 Sep 4.
The functional characterization of the GPCR interactome has predominantly focused on intracellular binding partners; however, the recent emergence of transsynaptic GPCR complexes represents an additional dimension to GPCR function that has previously been unaccounted for in drug discovery. Here, we characterize ELFN2 as a novel postsynaptic adhesion molecule with a distinct expression pattern throughout the brain and a selective binding with group III metabotropic glutamate receptors (mGluRs) in trans. Using a transcellular GPCR signaling platform, we report that ELFN2 critically alters group III mGluR secondary messenger signaling by directly altering G protein coupling kinetics and efficacy. Loss of ELFN2 in mice results in the selective downregulation of group III mGluRs and dysregulated glutamatergic synaptic transmission. Elfn2 knockout (Elfn2 KO) mice also feature a range of neuropsychiatric manifestations including seizure susceptibility, hyperactivity, and anxiety/compulsivity, which can be rescued by pharmacological augmentation of group III mGluRs. Thus, we conclude that extracellular transsynaptic scaffolding by ELFN2 in the brain is a cardinal organizational feature of group III mGluRs essential for their signaling properties and brain function.
GPCR 相互作用组的功能特征主要集中在细胞内结合伙伴上；然而，最近出现的突触间 GPCR 复合物代表了 GPCR 功能的另一个维度，这在药物发现中以前没有考虑到。在这里，我们将 ELFN2 表征为一种新型的突触后粘附分子，在整个大脑中具有独特的表达模式，并与跨突触的 III 组代谢型谷氨酸受体 (mGluR) 选择性结合。使用细胞间 GPCR 信号转导平台，我们报告说 ELFN2 通过直接改变 G 蛋白偶联动力学和效力，严重改变 III 组 mGluR 第二信使信号。在小鼠中缺失 ELFN2 会导致 III 组 mGluR 的选择性下调和谷氨酸能突触传递的失调。Elfn2 敲除 (Elfn2 KO) 小鼠还表现出一系列神经精神表现，包括易发性癫痫、多动和焦虑/强迫，这些表现可以通过药理学增强 III 组 mGluR 来挽救。因此，我们得出结论，ELFN2 在大脑中的细胞外跨突触支架是 III 组 mGluR 的一个主要组织特征，对于它们的信号特性和大脑功能至关重要。
