Rajadhyaksha A, Barczak A, Macías W, Leveque J C, Lewis S E, Konradi C
Molecular and Developmental Neuroscience Laboratory and Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
J Neurosci. 1999 Aug 1;19(15):6348-59. doi: 10.1523/JNEUROSCI.19-15-06348.1999.
The second messenger pathways linking receptor activation at the membrane to changes in the nucleus are just beginning to be unraveled in neurons. The work presented here attempts to identify in striatal neurons the pathways that mediate cAMP response element-binding protein (CREB) phosphorylation and gene expression in response to NMDA receptor activation. We investigated the phosphorylation of the transcription factor CREB, the expression of the immediate early gene c-fos, and the induction of a transfected reporter gene under the transcriptional control of CREB after stimulation of ionotropic glutamate receptors. We found that neither AMPA/kainate receptors nor NMDA receptors were able to stimulate independently a second messenger pathway that led to CREB phosphorylation or c-fos gene expression. Instead, we saw a consecutive pathway from AMPA/kainate receptors to NMDA receptors and from NMDA receptors to L-type Ca(2+) channels. AMPA/kainate receptors were involved in relieving the Mg(2+) block of NMDA receptors, and NMDA receptors triggered the opening of L-type Ca(2+) channels. The second messenger pathway that activates CREB phosphorylation and c-fos gene expression is likely activated by Ca(2+) entry through L-type Ca(2+) channels. We conclude that in primary striatal neurons glutamate-mediated signal transduction is dependent on functional L-type Ca(2+) channels.
将膜上受体激活与细胞核变化联系起来的第二信使途径在神经元中才刚刚开始被揭示。本文所展示的工作试图在纹状体神经元中确定介导环磷酸腺苷反应元件结合蛋白（CREB）磷酸化以及响应N-甲基-D-天冬氨酸（NMDA）受体激活的基因表达的途径。我们研究了离子型谷氨酸受体刺激后转录因子CREB的磷酸化、即刻早期基因c-fos的表达以及在CREB转录控制下转染报告基因的诱导情况。我们发现，α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）/海人藻酸受体和NMDA受体都不能独立刺激导致CREB磷酸化或c-fos基因表达的第二信使途径。相反，我们观察到一条从AMPA/海人藻酸受体到NMDA受体，再从NMDA受体到L型钙通道的连续途径。AMPA/海人藻酸受体参与解除NMDA受体的镁离子阻滞，而NMDA受体触发L型钙通道的开放。激活CREB磷酸化和c-fos基因表达的第二信使途径可能是由通过L型钙通道进入的钙离子激活的。我们得出结论，在原代纹状体神经元中，谷氨酸介导的信号转导依赖于功能性L型钙通道。
