Key role of the postsynaptic density scaffold proteins shank and homer in the functional architecture of Ca2+ homeostasis at dendritic spines in hippocampal neurons
Key role of the postsynaptic density scaffold proteins shank and homer in the functional architecture of Ca2+ homeostasis at dendritic spines in hippocampal neurons
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DOI：
10.1523/jneurosci.4822-04.2005
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发表时间：
2005-05-04
影响因子：
5.3
通讯作者：
Fagni, L
中科院分区：
文献类型：
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作者：
Sala, C;Roussignol, G;Fagni, L
突触后功能的一个关键方面，也是可塑性的重要方面，是树突棘内钙离子的分离，可归因于细胞内存储的释放。以往的研究表明，突触后密度(PSD)支架蛋白Shank1B和Hmer 1b在海马神经元中的过度表达可诱导脊髓成熟，包括细胞内钙通道三磷酸肌醇受体(IP3R)的移位。这些进程的结构和功能意义仍未确定。在这里，我们发现IP3R在其定位过程中伴随着其他内质网(ER)蛋白：钙泵肌质网钙ATPase、腔内钙结合蛋白Calreticlin、内质网寻址的绿色荧光蛋白，以及较少程度的膜伴侣钙结合蛋白。这些易位的特异性被Shank1片段和显性阴性的Hmer 1a所抑制。在Shank1B转基因神经元中，代谢性谷氨酸受体1/5(mGluRs1/5)的激活可以诱导IP3的产生，并随后从细胞内释放钙离子，从而引发钙依赖反应的显著增加：膜片钳显示的大K+通道的激活，以及细胞外信号调节蛋白激酶(ERK)的磷酸化。Shank1B和Hmer 1b的相互作用可能是连接位于脊椎的mGluRs1/5与IP3R的分子机制，使整个内质网池在PSD中整合，并对局部钙稳态和整体神经元信号转导产生影响。
A key aspect of postsynaptic function, also important for plasticity, is the segregation within dendritic spines of Ca2+ rises attributable to release from intracellular stores. Previous studies have shown that overexpression in hippocampal neurons of two postsynaptic density (PSD) scaffold proteins, Shank1B and Homer1b, induces spine maturation, including translocation of the intracellular Ca2+ channel inositol trisphosphate receptor (IP3R). The structural and functional significance of these processes remained undefined. Here, we show that in its relocation, IP3R is accompanied by other endoplasmic reticulum (ER) proteins: the Ca2+ pump sarcoendoplasmic reticulum calcium ATPase, the lumenal Ca2+-binding protein calreticulin, the ER lumen-addressed green fluorescent protein, and, to a lesser extent, the membrane chaperone calbindin. The specificity of these translocations was demonstrated by their inhibition by both a Shank1 fragment and the dominant-negative Homer1a. Activation in Shank1B-transfected neurons of the metabotropic glutamatergic receptors 1/5 (mGluRs1/5), which induce IP3 generation with ensuing Ca2+ release from the stores, triggered considerable increases in Ca2+-dependent responses: activation of the big K+ channel, which was revealed by patch clamping, and extracellular signal-regulated protein kinase (ERK) phosphorylation. The interaction of Shank1B and Homer1b appears as the molecular mechanism linking mGluRs1/5, strategically located in the spines, to IP3R with the integration of entire ER cisternas in the PSD and with consequences on both local Ca2+ homeostasis and overall neuronal signaling.