Presenilin-1 and intracellular calcium stores regulate neuronal glutamate uptake.
Presenilin-1 and intracellular calcium stores regulate neuronal glutamate uptake.
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Presenilin-1 和细胞内钙储备调节神经元谷氨酸的摄取。
DOI：
10.1046/j.1471-4159.2003.02279.x
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发表时间：
2004
影响因子：
4.7
通讯作者：
Cook,DavidG
中科院分区：
文献类型：
--
作者：
Yang,Yaxiong;Kinney,GregoryA;Spain,WilliamJ;Breitner,JohnCS;Cook,DavidG
高亲和力谷氨酸转运体对谷氨酸的摄取对于防止兴奋性毒性和维持正常的突触功能至关重要。我们发现了早老素-1(PS1)作为谷氨酸转运调节因子的新作用。与野生型神经元相比，PS1缺陷型神经元对谷氨酸的摄取减少了约50%。伽玛分泌酶抑制剂处理模拟了PS1缺乏对谷氨酸吸收的影响。由PS1缺乏或γ分泌酶抑制剂处理导致的PS1功能丧失，导致神经元谷氨酸转运体EAAC1的细胞表面表达相应减少。众所周知，PS1缺乏会减少细胞内的钙储存。为了探索PS1通过调节细胞内钙储存来影响谷氨酸摄取的可能性，我们研究了咖啡因、thapsigargin和SKF-96365处理神经元的效果。这些化合物以不同的方式耗尽细胞内的钙储存。尽管如此，每种处理都通过损害谷氨酸摄取和减少细胞表面EAAC1的表达来模仿PS1功能的丧失。阻断电压门控性钙通道、激活和抑制蛋白激酶C(PKC)、蛋白激酶A(PKA)均不影响神经元对谷氨酸的摄取。综上所述，这些发现表明，PS1和细胞内钙储存可能在调节谷氨酸摄取方面发挥重要作用，因此在限制谷氨酸在大脑中的毒性方面可能是重要的。
Glutamate uptake by high affinity glutamate transporters is essential for preventing excitotoxicity and maintaining normal synaptic function. We have discovered a novel role for presenilin‐1 (PS1) as a regulator of glutamate transport. PS1‐deficient neurons showed a decrease in glutamate uptake of approximately 50% compared to wild‐type neurons. Gamma‐secretase inhibitor treatment mimicked the effects of PS1 deficiency on glutamate uptake. PS1 loss‐of‐function, accomplished by PS1 deficiency or γ‐secretase inhibitor treatment, caused a corresponding decrease in cell surface expression of the neuronal glutamate transporter, EAAC1. PS1 deficiency is known to reduce intracellular calcium stores. To explore the possibility that PS1 influences glutamate uptake via regulation of intracellular calcium stores, we examined the effects of treating neurons with caffeine, thapsigargin, and SKF‐96365. These compounds depleted intracellular calcium stores by distinct means. Nonetheless, each treatment mimicked PS1 loss‐of‐function by impairing glutamate uptake and reducing EAAC1 expression at the cell surface. Blockade of voltage‐gated calcium channels, activation and inhibition of protein kinase C (PKC), and protein kinase A (PKA) all had no effect on glutamate uptake in neurons. Taken together, these findings indicate that PS1 and intracellular calcium stores may play a significant role in regulating glutamate uptake and therefore may be important in limiting glutamate toxicity in the brain.