Lindemeyer Kerstin, Leemhuis Jost, Löffler Steffen, Grass Nina, Nörenberg Wolfgang, Meyer Dieter K
Institute of Experimental and Clinical Pharmacology and Toxicology, Albert Ludwigs University, Freiburg, Germany.
Cereb Cortex. 2006 Nov;16(11):1662-77. doi: 10.1093/cercor/bhj103. Epub 2006 Jan 11.
Group I metabotropic glutamate receptors (mGluRIs) can be colocalized with ionotropic glutamate receptors in postsynaptic membranes. We have investigated whether mGluRIs alter the gene transcription induced by N-methyl-D-aspartate (NMDA) and (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid (AMPA) receptors in rat neocortical gamma-aminobutyric acid (GABA) interneurons. In cultures of dissociated interneurons, the mGluRI antagonists LY367385 and MPEP reduced the increase in phosphorylation of the transcription factor CREB induced by NMDA as well as the expression of the proenkephalin (PEnk) gene. In contrast, they enhanced the AMPA-induced CREB phosphorylation and PEnk gene expression. Stimulation of the mGluRIs was due to network activity that caused the release of endogenous glutamate and could be blocked by tetrodotoxin. In organotypic cultures of neocortex, endogenous glutamate enhanced the PEnk gene expression by acting on NMDA and AMPA receptors. These effects were modulated via mGluRIs. In patch-clamp experiments and in biochemical studies on receptor density, stimulation of mGluRIs acutely affected NMDA receptor currents but had no long-term effect on NMDA receptor density at the cell surface. In contrast, stimulation of mGluRIs decreased the density of AMPA receptors located at the cell surface. Our results suggest that mGluRIs regulate the glutamate-induced gene expression in neocortical interneurons in a physiologically relevant manner.
I 型代谢型谷氨酸受体（mGluRIs）可与离子型谷氨酸受体共定位于突触后膜。我们研究了 mGluRIs 是否会改变 N-甲基-D-天冬氨酸（NMDA）和（S）-α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体在大鼠新皮质γ-氨基丁酸（GABA）中间神经元中诱导的基因转录。在解离的中间神经元培养物中，mGluRI 拮抗剂 LY367385 和 MPEP 减少了由 NMDA 诱导的转录因子 CREB 磷酸化增加以及前脑啡肽（PEnk）基因的表达。相反，它们增强了 AMPA 诱导的 CREB 磷酸化和 PEnk 基因表达。mGluRIs 的刺激是由于网络活动导致内源性谷氨酸释放，并且可被河豚毒素阻断。在新皮质的器官型培养物中，内源性谷氨酸通过作用于 NMDA 和 AMPA 受体增强了 PEnk 基因表达。这些效应通过 mGluRIs 进行调节。在膜片钳实验以及受体密度的生化研究中，mGluRIs 的刺激急性影响 NMDA 受体电流，但对细胞表面的 NMDA 受体密度没有长期影响。相反，mGluRIs 的刺激降低了位于细胞表面的 AMPA 受体密度。我们的结果表明，mGluRIs 以生理相关的方式调节新皮质中间神经元中谷氨酸诱导的基因表达。
