EphA4 signaling regulates phospholipase Cγ1 activation, cofilin membrane association, and dendritic spine morphology
EphA4 signaling regulates phospholipase Cγ1 activation, cofilin membrane association, and dendritic spine morphology
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DOI：
10.1523/jneurosci.1170-07.2007
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发表时间：
2007-05-09
影响因子：
5.3
通讯作者：
Murai, Keith K.
中科院分区：
文献类型：
--
作者：
Zhou, Lei;Martinez, Sarah J.;Murai, Keith K.
称为树突棘的特化突触后结构是中枢神经系统突触处突触能神经支配的主要部位。以前的研究表明，棘迅速重塑其肌动蛋白细胞骨架，以改变其形状，这已与突触生理学的变化。然而，受体和信号中间体，重组肌动蛋白网络的刺才刚刚开始被确定。我们以前报道过EphA 4受体酪氨酸激酶调节脊柱形态。然而，EphA 4下游的信号传导途径诱导脊收缩肝配蛋白配体结合仍然知之甚少。在这里，我们证明，肝配蛋白刺激EphA 4导致招聘和激活的磷脂酶C γ 1（PLC γ 1）在异源细胞和海马切片。这种相互作用通过PLC γ 1的Src同源2结构域发生，并且需要EphA 4跨膜酪氨酸。在大脑中，PLC γ 1存在于突触体的多个隔室中，并且很容易在突触后密度组分中发现。与此一致，PLC活性是维持脊柱形态和肝配蛋白诱导的脊柱回缩所必需的。值得注意的是，EphA 4和PLC活性调节肌动蛋白解聚/切断因子cofilin与质膜的关联。由于cofilin先前已被牵连在结构可塑性的刺，这种信号传导可能使cofilin去肌动蛋白丝和重构刺的部位ephrin-EphA 4接触。
Specialized postsynaptic structures known as dendritic spines are the primary sites of glutamatergic innervation at synapses of the CNS. Previous studies have shown that spines rapidly remodel their actin cytoskeleton to modify their shape and this has been associated with changes in synaptic physiology. However, the receptors and signaling intermediates that restructure the actin network in spines are only beginning to be identified. We reported previously that the EphA4 receptor tyrosine kinase regulates spine morphology. However, the signaling pathways downstream of EphA4 that induce spine retraction on ephrin ligand binding remain poorly understood. Here, we demonstrate that ephrin stimulation of EphA4 leads to the recruitment and activation of phospholipase C gamma 1 (PLC gamma 1) in heterologous cells and in hippocampal slices. This interaction occurs through an Src homology 2 domain of PLC gamma 1 and requires the EphA4 juxtamembrane tyrosines. In the brain, PLC gamma 1 is found in multiple compartments of synaptosomes and is readily found in postsynaptic density fractions. Consistent with this, PLC activity is required for the maintenance of spine morphology and ephrin-induced spine retraction. Remarkably, EphA4 and PLC activity modulate the association of the actin depolymerizing/severing factor cofilin with the plasma membrane. Because cofilin has been implicated previously in the structural plasticity of spines, this signaling may enable cofilin to depolymerize actin filaments and restructure spines at sites of ephrin-EphA4 contact.