Brain insulin receptors and spatial memory - Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats
Brain insulin receptors and spatial memory - Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats
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DOI：
10.1074/jbc.274.49.34893
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发表时间：
1999-12-03
影响因子：
4.8
通讯作者：
Alkon, DL
中科院分区：
文献类型：
--
作者：
Zhao, WQ;Chen, H;Alkon, DL
从临床和基础研究中积累的证据已经间接地暗示胰岛素受体（IR）参与脑认知功能，包括学习和记忆（Wickelgren，I.（1998）Science 280，517-519），本研究调查了水迷宫训练后大鼠海马中IR表达、磷酸化和相关信号分子的相关变化。尽管IR蛋白在大多数前脑区域的分布与IR mRNA的分布相匹配，但在小脑皮质中发现IR mRNA和蛋白表达模式的分离。训练后，海马CA 1区和齿状回的IR mRNA表达上调，海马粗突触膜组分中LR蛋白的积累增加。在CA 1锥体神经元中，LR在特定细胞隔室（如核和树突区域）中的分布模式的变化仅在经过训练的动物中观察到。虽然IR显示出低水平的体内酪氨酸磷酸化，但在训练的动物中检测到胰岛素刺激的IR的体外Tyr磷酸化的增加，这表明学习可能诱导IR功能变化，例如增强受体敏感性。此外，检测到训练诱导的IR与Shc-66的免疫共沉淀，沿着体内Shc和促分裂原活化蛋白激酶的Tyr磷酸化的变化，以及训练后Shc-66、Shc-52和Grb-2在海马突触膜组分中的积累。这些结果表明，IR可能参与记忆加工通过激活其受体酪氨酸激酶活性，他们建议可能参与Shc/Grb-2/Ras/丝裂原活化蛋白激酶级联。
Evidence accumulated from clinical and basic research has indirectly implicated the insulin receptor (IR) in brain cognitive functions, including learning and memory (Wickelgren, I. (1998) Science 280, 517-519), The present study investigates correlative changes in IR expression, phosphorylation, and associated signaling molecules in the rat hippocampus following water maze training. Although the distribution of IR protein matched that of IR mRNA in most forebrain regions, a dissociation of the IR mRNA and protein expression patterns was found in the cerebellar cortex. After training, IR mRNA in the CA1 and dentate gyrus of the hippocampus was up-regulated, and there was increased accumulation of LR protein in the hippocampal crude synaptic membrane fraction. In the CA1 pyramidal neurons, changes in the distribution pattern of LR in particular cellular compartments, such as the nucleus and dendritic regions, was observed only in trained animals. Although IR showed a low level of in vivo tyrosine phosphorylation, an insulin-stimulated increase of in vitro Tyr phosphorylation of IR was detected in trained animals, suggesting that learning may induce IR functional changes, such as enhanced receptor sensitivity. Furthermore, a training-induced co-immunoprecipitation of IR with Shc-66 was detected, along with changes in in vivo Tyr phosphorylation of Shc and mitogen-activated protein kinase, as well as accumulation of Shc-66, Shc-52, and Grb-2 in hippocampal synaptic membrane fractions following training. These findings suggest that IR may participate in memory processing through activation of its receptor Tyr kinase activity, and they suggest possible engagement of Shc/Grb-2/Ras/mitogen-activated protein kinase cascades.