Department of Chemistry and Biochemistry , University of California, San Diego , 9500 Gilman Drive , La Jolla , California 92093-0358 , United States.
ACS Chem Neurosci. 2018 Dec 19;9(12):3086-3093. doi: 10.1021/acschemneuro.8b00295. Epub 2018 Aug 28.
Achieving molecular control over the formation of synaptic contacts in the nervous system can provide important insights into their regulation and can offer means for creating well-defined in vitro systems to evaluate modes of therapeutic intervention. Agrin-induced clustering of acetylcholine receptors (AChRs) at postsynaptic sites is a hallmark of the formation of the neuromuscular junction, a synapse between motoneurons and muscle cells. In addition to the cognate agrin receptor LRP4 (low-density lipoprotein receptor related protein-4), muscle cell heparan sulfate (HS) glycosaminoglycans (GAGs) have also been proposed to contribute to AChR clustering by acting as agrin co-receptors. Here, we provide direct evidence for the role of HS GAGs in agrin recruitment to the surface of myotubes, as well as their functional contributions toward AChR clustering. We also demonstrate that engineering of the myotube glycocalyx using synthetic HS GAG polymers can replace native HS structures to gain control over agrin-mediated AChR clustering.
实现神经系统中突触接触形成的分子控制，可以深入了解其调控机制，并提供创建明确的体外系统的手段，以评估治疗干预模式。神经递质乙酰胆碱受体 (AChR) 在突触后位点的聚集是运动神经元和肌肉细胞之间形成神经肌肉接头的标志。除了同源的 agrin 受体 LRP4（低密度脂蛋白受体相关蛋白-4）之外，肌肉细胞硫酸乙酰肝素 (HS) 糖胺聚糖 (GAG) 也被认为通过作为 agrin 共受体来促进 AChR 聚集。在这里，我们提供了 HS GAG 参与 agrin 募集到肌管表面以及它们对 AChR 聚集的功能贡献的直接证据。我们还证明，使用合成的 HS GAG 聚合物对肌管糖萼进行工程改造，可以替代天然 HS 结构，从而控制 agrin 介导的 AChR 聚集。
