Neurobiology Section, Division of Biology, University of California San Diego, La Jolla, CA 92093, USA.
Neuron. 2012 Mar 8;73(5):903-10. doi: 10.1016/j.neuron.2012.01.018.
Latrophilins (LPHNs) are a small family of G protein-coupled receptors known to mediate the massive synaptic exocytosis caused by the black widow spider venom α-latrotoxin, but their endogenous ligands and function remain unclear. Mutations in LPHN3 are strongly associated with attention deficit hyperactivity disorder, suggesting a role for latrophilins in human cognitive function. Using affinity chromatography and mass spectrometry, we identify the FLRT family of leucine-rich repeat transmembrane proteins as endogenous postsynaptic ligands for latrophilins. We demonstrate that the FLRT3 and LPHN3 ectodomains interact with high affinity in trans and that interference with this interaction using soluble recombinant LPHN3, LPHN3 shRNA, or FLRT3 shRNA reduces excitatory synapse density in cultured neurons. In addition, reducing FLRT3 levels with shRNA in vivo decreases afferent input strength and dendritic spine number in dentate granule cells. These observations indicate that LPHN3 and its ligand FLRT3 play an important role in glutamatergic synapse development.
拉托菲尔蛋白（LPHNs）是一小类 G 蛋白偶联受体，已知其介导黑寡妇蜘蛛毒液 α- latrotoxin 引起的大量突触胞吐，但它们的内源性配体和功能仍不清楚。LPHN3 突变与注意力缺陷多动障碍强烈相关，表明拉托菲尔蛋白在人类认知功能中起作用。我们使用亲和层析和质谱法鉴定富亮氨酸重复跨膜蛋白 FLRT 家族为拉托菲尔蛋白的内源性突触后配体。我们证明 FLRT3 和 LPHN3 外显子域以高亲和力相互作用，并且使用可溶性重组 LPHN3、LPHN3 shRNA 或 FLRT3 shRNA 干扰这种相互作用会减少培养神经元中的兴奋性突触密度。此外，体内用 shRNA 降低 FLRT3 水平会减少齿状回颗粒细胞中的传入输入强度和树突棘数量。这些观察结果表明，LPHN3 和其配体 FLRT3 在谷氨酸能突触发育中发挥重要作用。
