Glucagon-like peptide-1 cleavage product GLP-1 (9-36) amide enhances hippocampal long-term synaptic plasticity in correlation with suppression of Kv4.2 expression and eEF2 phosphorylation.
Glucagon-like peptide-1 cleavage product GLP-1 (9-36) amide enhances hippocampal long-term synaptic plasticity in correlation with suppression of Kv4.2 expression and eEF2 phosphorylation.
复制标题
作者：
Day SM;Yang W;Ewin S;Zhou X;Ma T
胰高血糖素样肽-1 （Glucagon-like peptide-1, GLP-1）是一种内源性肠道激素，是通过刺激胰岛素分泌维持葡萄糖稳态的关键调节因子。其天然裂解产物GLP-1（9-36）曾被认为是“生物无活性”代谢物，主要是由于其缺乏胰岛素促胰岛素作用和对GLP-1受体亲和力低，具有抗氧化和心血管保护等独特特性。关于GLP-1（9-36）在中枢神经系统中的作用知之甚少。在这里，我们报告了在成年小鼠中长期、系统地应用GLP-1（9-36）促进了海马长期增强（LTP）的诱导和维持阶段，LTP是突触可塑性的一种主要形式。相比之下，通过Morris水迷宫测试评估的空间学习和记忆，GLP-1（9-36）的使用并没有改变。在分子水平上，GLP-1（9-36）降低了海马中钾通道Kv4.2的蛋白水平，这与树突膜兴奋性升高有关。此外，GLP-1（9-36）处理抑制了mRNA翻译因子eEF2的磷酸化，这与从头合成蛋白质的能力增加有关。最后，我们发现使用GLP-1受体（GLP-1R）拮抗剂exendin(9-39)amide [EX(9-39)]可以减弱GLP-1（9-36）体内处理的ltp增强作用，提示其作为GLP-1R激动剂的作用。这些发现表明，GLP-1(9-36)，被认为是一种“生物无活性”肽，明显对海马体的神经元可塑性产生生理影响，海马体是大脑中学习和记忆的关键区域。
Glucagon-like peptide-1 (GLP-1) is an endogenous gut hormone and a key regulator in maintaining glucose homeostasis by stimulating insulin secretion. Its natural cleavage product GLP-1 (9-36), used to be considered a “bio-inactive” metabolite mainly due to its lack of insulinotropic effects and low affinity for GLP-1 receptors, possesses unique properties such as anti-oxidant and cardiovascular protection. Little is known about the role of GLP-1 (9-36) in central nervous system. Here we report that chronic, systemic application of GLP-1 (9-36) in adult mice facilitated both the induction and maintenance phases of hippocampal Long-term potentiation (LTP), a major form of synaptic plasticity. In contrast, spatial learning and memory, as assessed by the Morris water maze test, was not altered by GLP-1 (9-36) administration. At the molecular level, GLP-1 (9-36) reduced protein levels of the potassium channel Kv4.2 in hippocampus, which is linked to elevated dendritic membrane excitability. Moreover, GLP-1(9-36) treatment inhibited phosphorylation of mRNA translational factor eEF2, which is associated with increased capacity for de novo protein synthesis. Finally, we showed that the LTP-enhancing effects by GLP-1 (9-36) treatment in vivo were blunted by application of exendin(9-39)amide [EX(9-39)], the GLP-1 receptor (GLP-1R) antagonist, suggesting its role as a GLP-1R agonist. These findings demonstrate that GLP-1 (9-36), which was considered a “bio-inactive” peptide, clearly exerts physiological effects on neuronal plasticity in the hippocampus, a brain region critical for learning and memory.
登录
查看更多内容
影响因子：
4.8
作者：
Hansen, L;Deacon, CF;Holst, JJ
通讯作者：
Holst, JJ
影响因子：
16.2
作者：
Hoeffer, Charles A.;Tang, Wei;Klann, Eric
通讯作者：
Klann, Eric
DOI：
10.1007/978-1-4939-0897-4_6
发表时间：
2014-01-01
期刊：
MICROBIAL ENDOCRINOLOGY: THE MICROBIOTA-GUT-BRAIN AXIS IN HEALTH AND DISEASE
影响因子：
--
作者：
Al Omran, Yasser;Aziz, Qasim
通讯作者：
Aziz, Qasim
影响因子：
15.9
作者：
Hoeffer, Charles A.;Klann, Eric
通讯作者：
Klann, Eric
影响因子：
29
作者：
Hardie DG
通讯作者：
Hardie DG