Division of Glyco-Signal Research, Institute of Molecular Biomembrane and Glycobiology, Tohoku Pharmaceutical University, Sendai, Miyagi 981-8558, Japan.
J Biochem. 2012 Jul;152(1):63-72. doi: 10.1093/jb/mvs055. Epub 2012 May 9.
Gangliosides mediate neuronal differentiation and maturation and are indispensable for the maintenance of brain function and survival. As part of our ongoing efforts to understand signaling pathways related to ganglioside function, we recently demonstrated that neuronal cells react to exogenous gangliosides GT1b and GD1b. Both of these gangliosides are enriched in the synapse-forming area of the brain and induce Ca(2+) release from intracellular stores, activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and activation of cdc42 to promote reorganization of cytoskeletal actin and dendritic differentiation. Here, we show that bradykinin B2 receptors transduce these reactions as a mediator for ganglioside glycan signals. The B2 antagonist Hoe140 inhibited ganglioside-induced CaMKII activation, actin reorganization and early development of axon- and dendrite-like processes of primary cultured hippocampal neurons. Furthermore, we confirmed by yeast reporter assay that major b-series gangliosides, GT1b, GD1b and GD3, stimulated B2 bradykinin receptors. We hypothesize that this B2 receptor-mediated ganglioside signal transduction pathway is one mechanism that modulates neuronal differentiation and maturation.
神经节苷脂介导神经元的分化和成熟，对于维持大脑功能和生存是不可或缺的。作为我们正在进行的理解与神经节苷脂功能相关的信号通路的努力的一部分，我们最近证明神经元细胞对外源神经节苷脂 GT1b 和 GD1b 有反应。这两种神经节苷脂在大脑形成突触的区域丰富，并诱导细胞内储存的 Ca(2+)释放，激活 Ca(2+)/钙调蛋白依赖性蛋白激酶 II（CaMKII）和激活 cdc42 以促进细胞骨架肌动蛋白的重排和树突分化。在这里，我们表明缓激肽 B2 受体作为神经节苷脂糖信号的介质来传递这些反应。B2 拮抗剂 Hoe140 抑制神经节苷脂诱导的 CaMKII 激活、肌动蛋白重排以及原代培养海马神经元的轴突和树突样突起的早期发育。此外，我们通过酵母报告基因测定证实，主要的 b 系列神经节苷脂 GT1b、GD1b 和 GD3 刺激 B2 缓激肽受体。我们假设这种 B2 受体介导的神经节苷脂信号转导途径是调节神经元分化和成熟的一种机制。
