Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA.
Nat Neurosci. 2011 Jun;14(6):718-26. doi: 10.1038/nn.2825. Epub 2011 May 1.
Neuroligins, a family of postsynaptic adhesion molecules, are important in synaptogenesis through a well-characterized trans-synaptic interaction with neurexin. In addition, neuroligins are thought to drive postsynaptic assembly through binding of their intracellular domain to PSD-95. However, there is little direct evidence to support the functional necessity of the neuroligin intracellular domain in postsynaptic development. We found that presence of endogenous neuroligin obscured the study of exogenous mutated neuroligin. We therefore used chained microRNAs in rat organotypic hippocampal slices to generate a reduced background of endogenous neuroligin. On this reduced background, we found that neuroligin function was critically dependent on the cytoplasmic tail. However, this function required neither the PDZ ligand nor any other previously described cytoplasmic binding domain, but rather required a previously unknown conserved region. Mutation of a single critical residue in this region inhibited neuroligin-mediated excitatory synaptic potentiation. Finally, we found a functional distinction between neuroligins 1 and 3.
神经连接素是一类突触后黏附分子，通过与神经连接蛋白的一种特征性跨突触相互作用，在突触发生中发挥重要作用。此外，神经连接素被认为通过其细胞内结构域与 PSD-95 的结合来驱动突触后装配。然而，几乎没有直接证据支持神经连接素细胞内结构域在突触后发育中的功能必要性。我们发现内源性神经连接素的存在掩盖了对外源性突变神经连接素的研究。因此，我们使用大鼠器官型海马切片中的连锁 microRNAs 来产生内源性神经连接素的背景减少。在这种减少的背景下，我们发现神经连接素的功能严重依赖于细胞质尾部。然而，这种功能既不需要 PDZ 配体，也不需要任何其他先前描述的细胞质结合域，而是需要一个以前未知的保守区域。该区域中单个关键残基的突变抑制了神经连接素介导的兴奋性突触后增强。最后，我们发现神经连接素 1 和 3 之间存在功能上的区别。
