Weiner J A, Chun J
Graduate Program in Neurosciences, The Department of Pharmacology, School of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA.
Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5233-8. doi: 10.1073/pnas.96.9.5233.
Lysophosphatidic acid (LPA) is a bioactive phospholipid with properties of an extracellular growth factor for many cell lines, including those derived from neuroblastomas. However, the relevance of LPA signaling to the normal, developing nervous system is unknown, in part reflecting the previous unavailability of cloned receptor genes. Recent studies of the first such gene, encoding the G protein-coupled receptor LPA1/VZG-1 (lysophospholipid receptor A1/ventricular zone gene-1), revealed a major locus of expression in oligodendrocytes and Schwann cells (SCs) during development, suggesting an influence of LPA on these myelinating cells. Here we report that LPA (>/=10 nM) is a potent survival factor for cultured neonatal SCs, with survival activity equaling the maximal effect of neuregulin, the major peptide SC survival factor. LPA activates a pharmacologically defined signaling pathway in SCs, involving Gi and phosphoinositide 3-kinase. Moreover, LPA's effect depends on Akt, a downstream kinase that can mediate phosphoinositide 3-kinase-dependent survival, as demonstrated by both Western blot and transfection analyses. Overexpression of functional epitope-tagged LPA1/VZG-1 protein decreases SC apoptosis in response to serum withdrawal. These data demonstrate a role for extracellular LPA and its receptor LPA1/VZG-1 in SC survival and, more broadly, implicate G protein-coupled receptor-mediated lysophospholipid signaling as a significant mechanism in neural development.
溶血磷脂酸（LPA）是一种生物活性磷脂，对许多细胞系具有细胞外生长因子的特性，包括那些源自神经母细胞瘤的细胞系。然而，LPA信号传导与正常发育中的神经系统的相关性尚不清楚，部分原因是此前克隆的受体基因不可用。最近对第一个此类基因（编码G蛋白偶联受体LPA1/VZG-1，即溶血磷脂受体A1/脑室区基因-1）的研究表明，在发育过程中，少突胶质细胞和施万细胞（SCs）中有一个主要的表达位点，这表明LPA对这些髓鞘形成细胞有影响。在此，我们报告LPA（≥10 nM）是培养的新生SCs的一种有效存活因子，其存活活性等同于神经调节蛋白（主要的肽类SCs存活因子）的最大效应。LPA在SCs中激活一条药理学定义的信号通路，涉及Gi和磷酸肌醇3激酶。此外，LPA的作用依赖于Akt，一种下游激酶，可介导磷酸肌醇3激酶依赖性存活，蛋白质免疫印迹和转染分析均证明了这一点。功能性表位标记的LPA1/VZG-1蛋白的过表达可减少SCs因血清撤除而发生的凋亡。这些数据证明了细胞外LPA及其受体LPA1/VZG-1在SCs存活中的作用，更广泛地说，表明G蛋白偶联受体介导的溶血磷脂信号传导是神经发育中的一个重要机制。
