Kalirin binds the NR2B subunit of the NMDA receptor, altering its synaptic localization and function.
Kalirin binds the NR2B subunit of the NMDA receptor, altering its synaptic localization and function.
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DOI：
10.1523/jneurosci.3143-11.2011
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发表时间：
2011-08-31
期刊：
影响因子：
--
通讯作者：
Eipper BA
中科院分区：
文献类型：
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作者：
Kiraly DD;Lemtiri-Chlieh F;Levine ES;Mains RE;Eipper BA
树突棘迅速改变大小和形状的能力是调节突触强度的关键；这些形态变化依赖于肌动蛋白细胞骨架的重新排列。Kalirin-7(KAL7)是一种定位于突触后密度(PSD)的鸟嘌呤核苷酸交换因子，在体外和体内调节树突棘的形态。KAL7激活RAC并与PSD-95、DISC-1、AF-6和Arf6等多种PSD蛋白相互作用。KAL7(Kal7KO)基因缺失的小鼠在成瘾和学习模型中表现出海马LTP缺陷以及行为异常。来自Kal7KO小鼠的纯化的PSD含有NR2B的水平降低，NR2B是一种在LTP诱导中起关键作用的NMDA受体亚单位。在这里，我们证明了Kal7KO动物降低了皮质锥体神经元中依赖NR2B的NMDA受体电流的水平，以及NR2B在细胞表面表达的特异性缺陷。此外，我们证明，当动物在条件反射过程中使用NR2B特异性拮抗剂时，在Kal7KO小鼠中看到的条件性位置偏好和被动回避学习的基因差异被消除。最后，我们确定了KAL7的pleckstrin同源结构域与NR2B的胞浆C末端结构域之前的膜旁区域之间存在稳定的相互作用。NR2B与调节肌动蛋白细胞骨架的蛋白质结合是重要的，因为NMDA受体需要肌动蛋白完整性来实现突触定位和功能。这些研究表明，NMDA受体的NR2B亚单位与Kalirin之间存在着一种新的、功能上重要的相互作用，Kalirin是已知的对正常突触可塑性至关重要的蛋白质。
The ability of dendritic spines to change size and shape rapidly is critical in modulating synaptic strength; these morphological changes are dependent upon rearrangements of the actin cytoskeleton. Kalirin-7 (Kal7), a Rho guanine nucleotide exchange factor (GEF) localized to the postsynaptic density (PSD), modulates dendritic spine morphology in vitro and in vivo. Kal7 activates Rac and interacts with several PSD proteins including PSD-95, DISC-1, AF-6 and Arf6. Mice genetically lacking Kal7 (Kal7KO) exhibit deficient hippocampal LTP as well as behavioral abnormalities in models of addiction and learning. Purified PSDs from Kal7KO mice contain diminished levels of NR2B, an NMDA receptor subunit that plays a critical role in LTP induction. Here we demonstrate that Kal7KO animals have decreased levels of NR2B-dependent NMDA receptor currents in cortical pyramidal neurons as well as a specific deficit in cell-surface expression of NR2B. Additionally, we demonstrate that the genotypic differences in conditioned place preference and passive avoidance learning seen in Kal7KO mice are abrogated when animals are treated with an NR2B-specific antagonist during conditioning. Finally, we identify a stable interaction between the pleckstrin homology domain of Kal7 and the juxtamembrane region of NR2B preceding its cytosolic C-terminal domain. Binding of NR2B to a protein that modulates the actin cytoskeleton is important, as NMDA receptors require actin integrity for synaptic localization and function. These studies demonstrate a novel and functionally important interaction between the NR2B subunit of the NMDA receptor and Kalirin, proteins known to be essential for normal synaptic plasticity.