University Claude Bernard Lyon1, CGphiMC UMR CNRS 5534, 69622 Villeurbanne, France.
University Claude Bernard Lyon1, CGphiMC UMR CNRS 5534, 69622 Villeurbanne, France.
Neuron. 2015 Jun 17;86(6):1407-19. doi: 10.1016/j.neuron.2015.05.013. Epub 2015 May 28.
Positioning type A GABA receptors (GABA(A)Rs) in front of GABA release sites sets the strength of inhibitory synapses. The evolutionarily conserved Ce-Punctin/MADD-4 is an anterograde synaptic organizer that specifies GABAergic versus cholinergic identity of postsynaptic domains at the C. elegans neuromuscular junctions (NMJs). Here we show that the Ce-Punctin secreted by GABAergic motor neurons controls the clustering of GABA(A)Rs through the synaptic adhesion molecule neuroligin (NLG-1) and the netrin receptor UNC-40/DCC. The short isoform of Ce-Punctin binds and clusters NLG-1 postsynaptically at GABAergic NMJs. NLG-1 disruption causes a strong reduction of GABA(A)R content at GABAergic synapses. Ce-Punctin also binds and localizes UNC-40 receptors in the postsynaptic membrane of NMJs, which promotes the recruitment of GABA(A)Rs by NLG-1. Since the mammalian orthologs of these genes are expressed in the central nervous system and their mutations are implicated in neuropsychiatric diseases, this molecular pathway might have been evolutionarily conserved.
将 A 型 GABA 受体 (GABA(A)Rs) 定位在 GABA 释放位点前方可调节抑制性突触的强度。保守的 Ce-Punctin/MADD-4 是一种顺行性突触组织者，可在秀丽隐杆线虫神经肌肉接头 (NMJs) 处特异性调节 GABA 能与胆碱能的突触后结构。本研究表明 GABA 能运动神经元分泌的 Ce-Punctin 通过突触黏附分子神经粘连蛋白 (NLG-1) 和无翅型 MM 基因 40 (UNC-40)/DCC 控制 GABA(A)Rs 的聚集。Ce-Punctin 的短亚型与 GABA 能 NMJs 上的 NLG-1 形成突触后复合物，并聚集 NLG-1。NLG-1 缺失导致 GABA 能突触 GABA(A)R 含量显著减少。Ce-Punctin 还与 NMJs 突触后膜上的 UNC-40 受体结合并定位于该处，促进 NLG-1 募集 GABA(A)Rs。由于这些基因的哺乳动物同源物在中枢神经系统中表达，并且它们的突变与神经精神疾病有关，因此这种分子途径可能在进化上是保守的。
