Amyloid-β Decreases Cell-Surface AMPA Receptors by Increasing Intracellular Calcium and Phosphorylation of GluR2
Amyloid-β Decreases Cell-Surface AMPA Receptors by Increasing Intracellular Calcium and Phosphorylation of GluR2
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DOI：
10.3233/jad-2010-091654
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发表时间：
2010-01-01
影响因子：
4
通讯作者：
Small, David Henry
中科院分区：
文献类型：
--
作者：
Liu, Shi-Jie;Gasperini, Robert;Small, David Henry
α-氨基-3-羟基-5-甲基-4-异恶唑-丙酸受体（AMPAR）是突触功能和认知的关键调节剂。在阿尔茨海默病（AD）中，细胞表面AMPAR下调，然而这种下调的原因尚不清楚。在本研究中，我们发现A β显著降低海马神经元细胞表面AMPA型谷氨酸受体亚基2（GluR 2）的水平，并增加胞浆游离钙离子（[Ca 2 +]（i））的浓度。离子通道阻断剂（硝苯地平、河豚毒素、SKF 96365）降低[Ca 2 +]（i），增加细胞表面GluR 2水平，而L型电压门控钙通道激活剂Bay K 8644增加[Ca 2 +]（i），降低细胞表面GluR 2水平。A β和Bay K 8644增加GluR 2上丝氨酸-880（S880）的磷酸化，而硝苯地平。河豚毒素和SKF 96365降低S880磷酸化。最后，我们发现，双吲哚甲亚胺I（GF 109203 X，GFX），蛋白激酶C（PKC）的抑制剂阻断了细胞表面GluR 2的减少和磷酸化S880的增加诱导的A β和Bay K 8644。总之，这些结果表明，A β通过增加PKC介导的S880磷酸化来降低细胞表面GluR 2。我们的研究支持这样的观点，即A β诱导的胞浆[Ca 2 +]（i）升高可能通过降低突触处AMPAR的可用性来损害突触功能。AMPAR的这种减少可能有助于AD中观察到的认知功能下降。
alpha-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs) are key regulators of synaptic function and cognition. In Alzheimer's disease (AD), cell-surface AMPARs are downregulated, however the reason for this downregulation is not clear. In the present study, we found that A beta significantly decreased levels of the cell-surface AMPA-type glutamate receptor subunit 2 (GluR2), and increased the concentration of free cytosolic calcium ion ([Ca2+](i)) in hippocampal neurons. Ion channel blockers (nifedipine, tetrodotoxin, SKF96365) decreased [Ca2+](i) and increased the level of cell-surface GluR2, whereas Bay K 8644, an activator of L-type voltage-gated calcium channels increased [Ca2+](i) and decreased cell-surface GluR2. A beta and Bay K 8644 increased phosphorylation of serine-880 (S880) on GluR2, whereas the nifedipine. tetrodotoxin and SKF96365 decreased S880 phosphorylation. Finally, we found that bisindolylmeimide I (GF 109203X, GFX), an inhibitor of protein kinase C (PKC) blocked both the decrease in cell-surface GluR2 and the increase in phospho-S880 induced by A beta and Bay K 8644. Taken together, these results demonstrate that A beta decreases cell-surface GluR2 by increasing PKC-mediated phosphorylation of S880. Our study supports the view that a rise in cytosolic [Ca2+](i) induced by A beta could impair synaptic function by decreasing the availability of AMPARs at the synapse. This decrease in AMPARs may contribute to the decline in cognitive function seen in AD.