The FGF receptor uses the endocannabinoid signaling system to couple to an axonal growth response.
The FGF receptor uses the endocannabinoid signaling system to couple to an axonal growth response.
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DOI：
10.1083/jcb.200210164
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发表时间：
2003-02-17
影响因子：
7.8
通讯作者：
Doherty, Patrick
中科院分区：
文献类型：
--
作者：
Williams, Emma-Jane;Walsh, Frank S;Doherty, Patrick
DAG脂肪酶活性在体外和体内轴突生长控制和指导中的关键作用已经确立。例如，DAG脂肪酶活性是FGF刺激的钙流入神经元生长锥所必需的，并且这种反应对于轴突生长反应是必要的和足够的。将DAG水解与钙反应结合的机制尚不清楚。DAG在sn-1位的初始水解（通过DAG脂肪酶）将产生2-花生四烯酰甘油，并且该分子被充分确立为脑中的内源性大麻素受体激动剂。在本文中，我们表明，在大鼠小脑颗粒神经元，CB 1大麻素受体拮抗剂抑制轴突生长的N-钙粘蛋白和FGF 2刺激的反应。此外，三种CB 1受体激动剂在FGF受体活化下游但在钙流入细胞上游的步骤模拟N-钙粘蛋白/FGF 2反应。相比之下，我们没有发现CB 1受体将TrkB神经营养因子受体偶联到相同神经元中的轴突生长反应的证据。CB 1受体可以将活化的FGF受体与轴突生长反应偶联的观察结果提出了新的治疗机会。
Akey role for DAG lipase activity in the control of axonal growth and guidance in vitro and in vivo has been established. For example, DAG lipase activity is required for FGF-stimulated calcium influx into neuronal growth cones, and this response is both necessary and sufficient for an axonal growth response. The mechanism that couples the hydrolysis of DAG to the calcium response is not known. The initial hydrolysis of DAG at the sn-1 position (by DAG lipase) will generate 2-arachidonylglycerol, and this molecule is well established as an endogenous cannabinoid receptor agonist in the brain. In the present paper, we show that in rat cerebellar granule neurons, CB1 cannabinoid receptor antagonists inhibit axonal growth responses stimulated by N-cadherin and FGF2. Furthermore, three CB1 receptor agonists mimic the N-cadherin/FGF2 response at a step downstream from FGF receptor activation, but upstream from calcium influx into cells. In contrast, we could find no evidence for the CB1 receptor coupling the TrkB neurotrophin receptor to an axonal growth response in the same neurons. The observation that the CB1 receptor can couple the activated FGF receptor to an axonal growth response raises novel therapeutic opportunities.