Netrin-1-mediated axon outgrowth and cAMP production requires interaction with adenosine A2b receptor
Netrin-1-mediated axon outgrowth and cAMP production requires interaction with adenosine A2b receptor
复制标题
DOI：
10.1038/35037600
复制
发表时间：
2000-10-12
期刊：
影响因子：
64.8
通讯作者：
Mehlen, P
中科院分区：
文献类型：
--
作者：
Corset, V;Nguyen-ba-Charvet, KT;Mehlen, P
netrins是层粘连蛋白相关分泌蛋白家族，在控制轴突伸长和寻路中至关重要（1-4）。根据许多观察结果，包括在抗DCC抗血清存在下抑制netrin-1介导的轴突生长和吸引（5-7），DCC和netrin-1敲除小鼠中神经系统缺陷的相似性（4，8）和受体交换实验的结果（9），提出DCC（在结肠直肠癌中缺失）蛋白作为netrin-1的受体。以前的研究未能显示DCC与netrin-1的直接相互作用（参考文献10），这表明可能存在其他受体或辅助受体。在这里，我们发现DCC与膜相关的腺苷A2 b受体相互作用，这是一种G蛋白偶联受体，在结合腺苷时诱导cAMP积累（11）。我们表明，A2 b实际上是一个netrin-1受体，并诱导cAMP积累结合netrin-1。最后，我们表明，netrin-1依赖的生长脊髓背侧轴突直接涉及A2 b。总之，我们的研究结果表明，netrin-1的生长促进功能可能需要一个受体复合物含有DCC和A2 b。
The netrins, a family of laminin-related secreted proteins, are critical in controlling axon elongation and pathfinding(1-4). The DCC (for deleted in colorectal cancer) protein was proposed as a receptor for netrin-1 in the light of many observations including the inhibition of netrin-1-mediated axon outgrowth and attraction in the presence of an anti-DCC antiserum(5-7), the similitude of nervous system defects in DCC and netrin-1 knockout mice(4,8) and the results of receptor swapping experiments(9). Previous studies have failed to show a direct interaction of DCC with netrin-1 (ref. 10), suggesting the possibility of an additional receptor or coreceptor. Here we show that DCC interacts with the membrane-associated adenosine A2b receptor, a G-protein-coupled receptor that induces cAMP accumulation on binding adenosine(11). We show that A2b is actually a netrin-1 receptor and induces cAMP accumulation on binding netrin-1. Finally, we show that netrin-1-dependent outgrowth of dorsal spinal cord axons directly involves A2b. Together our results indicate that the growth-promoting function of netrin-1 may require a receptor complex containing DCC and A2b.