Axonal targeting of Caspr2 in hippocampal neurons via selective somatodendritic endocytosis
Axonal targeting of Caspr2 in hippocampal neurons via selective somatodendritic endocytosis
复制标题
DOI：
10.1242/jcs.050526
复制
发表时间：
2009-09-15
影响因子：
4
通讯作者：
Faivre-Sarrailh, Catherine
中科院分区：
文献类型：
--
作者：
Bel, Christophe;Oguievetskaia, Ksenia;Faivre-Sarrailh, Catherine
接触蛋白相关蛋白2 （Caspr2）是一种神经元膜蛋白，在自闭症和相关疾病中发生突变。虽然它在Ranvier的近aparanodes高度富集，对shaker型K+通道聚集至关重要，但对其功能和调控知之甚少。在本研究中，我们使用细胞外血凝素（HA）标记的Caspr2构建物检测了Caspr2在海马神经元中的极化表达。我们发现Caspr2靶向轴突表面，但与体突腔室的早期核内体共定位。使用Dynamin-1突变体或Dynasore处理抑制内吞作用可阻止Caspr2从树突和细胞体内化。我们发现了一个短序列包含在4.1 b结合域中，这是Caspr2内吞作用所必需的。该序列包含Thr1292上的蛋白激酶C （PKC）底物基序，该残基的点突变或PKC抑制剂的处理阻止了Caspr2的体树突内化。因此，pkc依赖性转运Caspr2是其在海马神经元中极化表达的基础。
Contactin-associated protein 2 (Caspr2) is a neuronal membrane protein that is mutated in autism and related disorders. Although it is highly enriched at juxtaparanodes of Ranvier where it is essential for Shaker-type K+ channel clustering, little is known about its function and regulation. In the present study, we examined the polarized expression of Caspr2 in hippocampal neurons using extracellular hemagglutinin (HA)-tagged Caspr2 constructs. We found that Caspr2 was targeted to the axonal surface, but colocalized with early endosomes in the somatodendritic compartment. The inhibition of endocytosis using a Dynamin-1 mutant or treatment with Dynasore prevented Caspr2 internalization from the dendrites and cell body. We identified a short sequence included into the 4.1B-binding domain that is required for the endocytosis of Caspr2. This sequence contains a protein kinase C (PKC) substrate motif on Thr1292, and point mutation of this residue or treatment with a PKC inhibitor prevented the somatodendritic internalization of Caspr2. Thus, the PKC-dependent trafficking of Caspr2 underlies its polarized expression in hippocampal neurons.