Soluble Adenylyl Cyclase Is Necessary and Sufficient to Overcome the Block of Axonal Growth by Myelin-Associated Factors
Soluble Adenylyl Cyclase Is Necessary and Sufficient to Overcome the Block of Axonal Growth by Myelin-Associated Factors
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DOI：
10.1523/jneurosci.1434-14.2014
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发表时间：
2014-07-09
影响因子：
5.3
通讯作者：
Filbin, Marie T.
中科院分区：
文献类型：
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作者：
Martinez, Jennifer;Stessin, Alexander M.;Filbin, Marie T.
中枢神经系统中的神经元在受伤后不会再生；髓磷脂中的抑制蛋白（例如髓磷脂相关糖蛋白（MAG））会阻止再生。提高第二信使 cAMP 的神经元水平可以克服轴突生长受阻的情况。提高 cAMP 的一种方法是用神经营养因子（例如脑源性神经营养因子 (BDNF)）预处理神经元。然而，多效性和较差的生物利用度使得神经营养因子在体内的外源给药存在问题；因此，必须考虑替代目标。在神经元中，两个腺苷酸环化酶家族合成 cAMP、跨膜腺苷酸环化酶 (tmAC) 和可溶性腺苷酸环化酶 (sAC)。在这里，我们证明 sAC 是 BDNF 克服 MAG 依赖性神经突生长抑制的 cAMP 的重要来源。提高大鼠和小鼠神经元中的 sAC 足以在体外诱导髓磷脂上的神经突生长，并促进体内再生。这些结果表明 sAC 刺激剂可能代表一种促进轴突生长和再生的新治疗策略。
Neurons in the CNS do not regenerate following injury; regeneration is blocked by inhibitory proteins in myelin, such as myelin-associated glycoprotein (MAG). Elevating neuronal levels of the second messenger cAMP overcomes this blocked axonal outgrowth. One way to elevate cAMP is pretreating neurons with neurotrophins, such as brain-derived neurotrophic factor (BDNF). However, pleiotropic effects and poor bioavailability make exogenous administration of neurotrophins in vivo problematic; therefore, alternative targets must be considered. In neurons, two families of adenylyl cyclases synthesize cAMP, transmembrane adenylyl cyclases (tmACs), and soluble adenylyl cyclase (sAC). Here, we demonstrate that sACis the essential source of cAMP for BDNF to over come MAG-dependent inhibition of neurite outgrowth. Elevating sAC in rat and mouse neurons is sufficient to induce neurite outgrowth on myelin in vitro and promotes regeneration in vivo. These results suggest that stimulators of sAC might represent a novel therapeutic strategy to promote axonal growth and regeneration.