Physiology Department, Medical School, University of Patras, Rio, Patras, Greece.
Neuroscience. 2009 Nov 10;163(4):1135-45. doi: 10.1016/j.neuroscience.2009.07.056. Epub 2009 Jul 30.
Interactions between dopamine and glutamate receptors are essential for the prefrontal cortical (PFC) and hippocampal cognitive functions. In order to understand the molecular basis of dopamine/glutamate interactions in rat PFC and hippocampus, we investigated (a) the effect of in vitro dopamine D1 receptor stimulation on glutamate N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunits' phosphorylation and (b) the signal transduction pathway underlying these interactions, by examining the involvement of D1-extracellular regulated kinase 1/2 (ERK1/2) and D1/protein kinase A (PKA)/dopamine- and cyclic AMP-regulated phosphoprotein-32 (DARPP-32) signaling pathways. Furthermore, we compared the D1/NMDA/AMPA receptor interactions seen in PFC and hippocampus with those appearing in striatum, in which the D1 receptors' density is the highest within the mammalian brain. Our results showed that stimulation of D1 receptor by the specific agonist SKF38393 (10 microM) in PFC and hippocampal slices significantly increased the phosphorylation state of NR1ser897 and NR2Bser1303 subunits of NMDA receptor and of the GLUR1 (ser831 and ser845) subunit of AMPA receptor, as well as of ERK1/2, but not of DARPP-32. Interestingly, co-stimulation of D1 and NMDA receptors with an ineffective dose of SKF38393 (2 microM) and NMDA (5 microM) respectively, elevated further the phosphorylation level of NMDA and AMPA receptor subunits, as well as of ERK1/2, but not of DARPP-32. The D1- and D1/NMDA-induced phosphorylations were totally inhibited by SL327 (specific ERK1/2 inhibitor). Conversely, in striatal slices our data confirm that the D1-mediated phosphorylation of NMDA and AMPA receptor subunits relies on D1/PKA/DARPP-32 signaling. In conclusion, in PFC and hippocampus: (a) a strong synergistic interaction of D1 and NMDA receptors exists, which results in a significant ERK1/2 pathway activation, (b) the D1 and the D1/NMDA receptor-induced phosphorylation of NMDA and AMPA receptor subunits seems to rely on ERK1/2 signaling and could to some extent underlie the enhancement of NMDA and AMPA receptor currents mediated by D1 receptor activation.
多巴胺和谷氨酸受体之间的相互作用对于前额叶皮层（PFC）和海马体的认知功能至关重要。为了了解多巴胺/谷氨酸相互作用在大鼠 PFC 和海马体中的分子基础，我们研究了（a）体外多巴胺 D1 受体刺激对谷氨酸 N-甲基-D-天冬氨酸（NMDA）和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体亚基磷酸化的影响，以及（b）这些相互作用的信号转导途径，通过检查 D1-细胞外调节激酶 1/2（ERK1/2）和 D1/蛋白激酶 A（PKA）/多巴胺和环 AMP 调节磷蛋白-32（DARPP-32）信号通路的参与。此外，我们比较了 PFC 和海马体中出现的 D1/NMDA/AMPA 受体相互作用与纹状体中出现的相互作用，纹状体是哺乳动物大脑中 D1 受体密度最高的区域。我们的结果表明，在 PFC 和海马切片中，特异性激动剂 SKF38393（10 μM）刺激 D1 受体可显著增加 NMDA 受体 NR1ser897 和 NR2Bser1303 亚基以及 AMPA 受体 GLUR1（ser831 和 ser845）亚基的磷酸化状态，以及 ERK1/2，但不包括 DARPP-32。有趣的是，用无效剂量的 SKF38393（2 μM）和 NMDA（5 μM）分别共同刺激 D1 和 NMDA 受体，进一步提高了 NMDA 和 AMPA 受体亚基以及 ERK1/2 的磷酸化水平，但不包括 DARPP-32。D1 和 D1/NMDA 诱导的磷酸化完全被 SL327（特异性 ERK1/2 抑制剂）抑制。相反，在纹状体切片中，我们的数据证实 D1 介导的 NMDA 和 AMPA 受体亚基的磷酸化依赖于 D1/PKA/DARPP-32 信号。总之，在 PFC 和海马体中：（a）D1 和 NMDA 受体之间存在强烈的协同相互作用，导致 ERK1/2 途径的显著激活；（b）D1 和 D1/NMDA 受体诱导的 NMDA 和 AMPA 受体亚基的磷酸化似乎依赖于 ERK1/2 信号，并且在某种程度上可能是 D1 受体激活介导的 NMDA 和 AMPA 受体电流增强的基础。
