Li Shaomin, Tian Xuejun, Hartley Dean M, Feig Larry A
Department of Biochemistry, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
J Neurosci. 2006 Feb 8;26(6):1721-9. doi: 10.1523/JNEUROSCI.3990-05.2006.
NMDA-type glutamate receptors (NMDARs) contribute to many forms of long-term potentiation (LTP) and long-term depression (LTD). NMDARs are heteromers containing calcium-permeating neuronal receptor 1 (NR1) subunits and a variety of NR2 subunits. Evidence suggests that, in the CA1 region of the hippocampus, NR2A-containing NMDARs promote LTP whereas NR2B-containing receptors promote LTD. However, the calcium sensors that distinguish between these signals to promote the appropriate form of synaptic plasticity are not known. Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) and Ras-GRF2 are highly similar calcium-stimulated exchange factors that activate Ras and Rac GTPases. Here, using a set of Ras-GRF knock-out mice, we show that Ras-GRF2 contributes predominantly to the induction of NMDAR-dependent LTP, whereas Ras-GRF1 contributes predominantly to the induction of NMDAR-dependent LTD in the CA1 region of the hippocampus of postpubescent mice (postnatal days 25-36). In contrast, neither Ras-GRF protein influences synaptic plasticity in prepubescent mice (postnatal days 14-18). Ras-GRF2 mediates signaling from (R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl-phosphonic acid-sensitive (NVP-AAM077-sensitive) (NR2A-containing) NMDARs to the Ras effector extracellular signal-related protein kinase 1/2 (Erk1/2) mitogen-activated protein (MAP) kinase, a promoter of NMDAR-induced LTP at this site. In contrast, Ras-GRF1 mediates signaling from ifenprodil-sensitive (NR2B-containing) NMDARs to the Rac effector p38 MAP kinase, a promoter of LTD. These findings show that, despite their similar functional domain organization, Ras-GRF1 and Ras-GRF2 mediate opposing forms of synaptic plasticity by coupling different classes of NMDARs to distinct MAP kinase pathways. Moreover, the postnatal appearance of Ras-GRF-dependent LTP and LTD coincides with the emergence of hippocampal-dependent behavior, implying that Ras-GRF proteins contribute to forms of synaptic plasticity that are required specifically for mature hippocampal function.
N-甲基-D-天冬氨酸（NMDA）型谷氨酸受体（NMDARs）参与多种形式的长时程增强（LTP）和长时程抑制（LTD）。NMDARs是异聚体，包含钙离子通透的神经元受体1（NR1）亚基和多种NR2亚基。有证据表明，在海马体的CA1区域，含NR2A的NMDARs促进LTP，而含NR2B的受体促进LTD。然而，区分这些信号以促进适当形式突触可塑性的钙传感器尚不清楚。Ras-鸟嘌呤核苷酸释放因子1（Ras-GRF1）和Ras-鸟嘌呤核苷酸释放因子2（Ras-GRF2）是高度相似的钙刺激交换因子，可激活Ras和Rac GTP酶。在此，我们使用一组Ras-GRF基因敲除小鼠，发现Ras-GRF2主要促成青春期后小鼠（出生后第25 - 36天）海马体CA1区域NMDAR依赖的LTP的诱导，而Ras-GRF1主要促成该区域NMDAR依赖的LTD的诱导。相比之下，两种Ras-GRF蛋白均不影响青春期前小鼠（出生后第14 - 18天）的突触可塑性。Ras-GRF2介导来自（R）-[（S）-1-（4-溴苯基）-乙氨基] -（2,3-二氧代-1,2,3,4-四氢喹喔啉-5-基）-甲基膦酸敏感的（NVP-AAM077敏感的）（含NR2A的）NMDARs的信号传导至Ras效应器细胞外信号调节激酶1/2（Erk1/2）丝裂原活化蛋白（MAP）激酶，后者是该位点NMDAR诱导的LTP的促进因子。相比之下，Ras-GRF1介导来自ifenprodil敏感的（含NR2B的）NMDARs的信号传导至Rac效应器p38 MAP激酶，后者是LTD的促进因子。这些发现表明，尽管Ras-GRF1和Ras-GRF2具有相似的功能域结构，但它们通过将不同类别的NMDARs与不同的MAP激酶途径偶联，介导相反形式的突触可塑性。此外，Ras-GRF依赖的LTP和LTD在出生后的出现与海马体依赖行为的出现相一致，这意味着Ras-GRF蛋白促成了成熟海马体功能所特需的突触可塑性形式。
