Endocannabinoid-Goα signalling inhibits axon regeneration in Caenorhabditis elegans by antagonizing Gqα-PKC-JNK signalling.
Endocannabinoid-Goα signalling inhibits axon regeneration in Caenorhabditis elegans by antagonizing Gqα-PKC-JNK signalling.
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DOI：
10.1038/ncomms2136
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发表时间：
2012
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
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神经元在损伤后再生其轴突的能力由促进和抑制再生的细胞途径之间的平衡决定。在秀丽隐杆线虫中，轴突再生受到c-Jun N-末端激酶促分裂原活化蛋白激酶途径的正调控，该途径由生长因子受体酪氨酸激酶信号转导激活。在这里，我们表明，脂肪酸酰胺水解酶-1，参与内源性大麻素anandamide（花生四烯酸乙醇酰胺）的降解酶，调节激光轴突切断后γ-氨基丁酸神经元的轴突再生反应。外源性花生四烯酰乙醇酰胺通过Goα亚基果阿-1抑制轴突再生，其拮抗Gqα亚基EGL-30。我们进一步证明了蛋白激酶C在Gqα下游发挥作用，并通过磷酸化MLK-1激活MLK-1-MEK-1-KGB-1 c-Jun N-末端激酶途径。我们的研究结果表明，花生四烯酰乙醇酰胺诱导的G蛋白信号转导通路具有抑制发育后轴突再生的作用。C. elegans是正调控JNK/MAP激酶途径。Pastuhov及其同事将内源性大麻素anandamide确定为该途径的负调节剂，并表明anandamide抑制轴突切断后成熟神经元的轴突再生。
The ability of neurons to regenerate their axons after injury is determined by a balance between cellular pathways that promote and those that inhibit regeneration. In Caenorhabditis elegans, axon regeneration is positively regulated by the c-Jun N-terminal kinase mitogen activated protein kinase pathway, which is activated by growth factor-receptor tyrosine kinase signalling. Here we show that fatty acid amide hydrolase-1, an enzyme involved in the degradation of the endocannabinoid anandamide (arachidonoyl ethanolamide), regulates the axon regeneration response of γ-aminobutyric acid neurons after laser axotomy. Exogenous arachidonoyl ethanolamide inhibits axon regeneration via the Goα subunit GOA-1, which antagonizes the Gqα subunit EGL-30. We further demonstrate that protein kinase C functions downstream of Gqα and activates the MLK-1-MEK-1-KGB-1 c-Jun N-terminal kinase pathway by phosphorylating MLK-1. Our results show that arachidonoyl ethanolamide induction of a G protein signal transduction pathway has a role in the inhibition of post-development axon regeneration. Axon regeneration in C. elegans is positively regulated by the JNK/MAP kinase pathway. Pastuhov and colleagues identify the endocannabinoid anandamide as a negative regulator of this pathway and show that anandamide inhibits axon regeneration in mature neurons after axotomy.
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