Phospholipase D2 functions as a downstream signaling molecule of MAP kinase pathway in L1‐stimulated neurite outgrowth of cerebellar granule neurons
Phospholipase D2 functions as a downstream signaling molecule of MAP kinase pathway in L1‐stimulated neurite outgrowth of cerebellar granule neurons
复制标题
DOI：
10.1111/j.1471-4159.2004.02308.x
复制
发表时间：
2004-04
影响因子：
4.7
通讯作者：
Hiroshi Watanabe;Masakazu Yamazaki;Hideyuki Miyazaki;Chihiro Arikawa;K. Itoh;Takehiko Sasaki;T. Maehama;M. Frohman;Y. Kanaho
中科院分区：
文献类型：
--
作者：
Hiroshi Watanabe;Masakazu Yamazaki;Hideyuki Miyazaki;Chihiro Arikawa;K. Itoh;Takehiko Sasaki;T. Maehama;M. Frohman;Y. Kanaho
刺激小脑颗粒神经元（CGNs）中的神经元细胞粘附分子L1可增强神经突生长，而这种反应可被伯醇乙醇抑制。由于伯醇抑制磷脂酶D（PLD）形成信号脂质磷脂酸（PA），这一观察结果促使我们研究PLD是否在CGN中L1介导的神经突生长中发挥作用。在出生后第8天的小鼠小脑中，PLD 2蛋白大量表达，而PLD 1的表达未检测到。L1刺激的神经突生长受到伯醇和脂肪酶缺陷型PLD 2过表达的抑制。通过直接PA应用或野生型PLD 2的过表达增加细胞PA水平模拟了L1依赖的神经突生长刺激。此外，发现CGN中的L1刺激伴随着细胞外信号调节激酶（ERK）的磷酸化增加PLD活性，这两者都被MAP激酶-ERK激酶（MEK）抑制剂抑制。这些结果提供了证据，证明PLD 2作为ERK的下游信号分子介导CGN的L1依赖性神经突生长，这一机制可能与酒精相关的神经发育障碍有关。
Stimulation of the neuronal cell adhesion molecule L1 in cerebellar granule neurons (CGNs) enhances neurite outgrowth and this response is inhibited by the primary alcohol ethanol. Because primary alcohols suppress the formation of the signaling lipid phosphatidic acid (PA) by phospholipase D (PLD), this observation prompted us to investigate whether PLD plays a role in the L1‐mediated neurite outgrowth in CGNs. In the cerebellum of postnatal day 8 mice, PLD2 protein was abundantly expressed, while PLD1 expression was not detected. The L1‐stimulated neurite outgrowth was inhibited by primary alcohols and by overexpression of lipase‐deficient PLD2. Increases in cellular PA levels by direct PA application or overexpression of wild‐type PLD2 mimicked the L1‐dependent stimulation of neurite outgrowth. Furthermore, it was found that L1 stimulation in CGNs increased PLD activity concomitantly with phosphorylation of extracellular signal‐regulated kinase (ERK), both of which were inhibited by the MAP kinase‐ERK kinase (MEK) inhibitor. These results provide evidence that PLD2 functions as a downstream signaling molecule of ERK to mediate the L1‐dependent neurite outgrowth of CGNs, a mechanism that may be related to alcohol‐related neurodevelopmental disorders.