Subtype-dependence of N-methyl-D-aspartate receptor modulation by pregnenolone sulfate
Subtype-dependence of N-methyl-D-aspartate receptor modulation by pregnenolone sulfate
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DOI：
10.1016/j.neuroscience.2005.08.058
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发表时间：
2006-01-01
期刊：
影响因子：
3.3
通讯作者：
Vyklicky, L
中科院分区：
文献类型：
--
作者：
Horak, M;Vlcek, K;Vyklicky, L
N-甲基-D-天冬氨酸受体在突触发生、突触可塑性和兴奋性毒性中起关键作用。它们是NR 1与NR 2A-D和/或NR 3A-B亚基组合的异聚体复合物。亚基组成决定了N-甲基-D-天冬氨酸受体通道复合物的生物物理和药理学性质。在这项研究中，我们报告说，在人胚肾HEK 293细胞中表达的重组大鼠N-甲基-D-天冬氨酸受体介导的反应是由天然存在的神经甾体硫酸双烯醇酮的差异影响。我们发现，1 mM谷氨酸诱导的NR 1 -1a/NR 2A和NR 1 -1a/NR 2B受体的反应是增强5 - 8倍以上的硫酸双烯醇酮比NR 1 -1a/NR 2C和NR 1 -1a/NR 2D受体的反应，硫酸双烯醇酮的浓度没有差异，产生50%的增强。除了增强作用之外，硫酸双烯醇酮还对重组N-甲基-D-天冬氨酸受体具有抑制作用，产生50%抑制的硫酸双烯醇酮浓度值为NR 1/NR 2D = NR 1/NR 2C <NR 1/NR 2B <NR 1/NR 2A。此外，我们表明，NR 2亚基的第三和第四跨膜结构域之间的细胞外环的结构是硫酸双烯醇酮的增强和抑制作用的关键。硫酸双烯醇酮的调节作用与该神经类固醇作用于N-甲基-D-天冬氨酸受体的两个不同结合位点的模型一致。这些数据提供了深入了解硫酸双烯醇酮和相关硫酸化神经类固醇调节N-甲基-D-天冬氨酸受体通道活性的机制。(c)2005由Elsevier Ltd代表IBRO出版。
N-methyl-D-aspartate receptors play a critical role in synaptogenesis, synaptic plasticity, and excitotoxicity. They are heteromeric complexes of NR1 combined with NR2A-D and/or NR3A-B subunits. The subunit composition determines the biophysical and pharmacological properties of the N-methyl-D-aspartate receptor channel complex. In this study, we report that responses mediated by recombinant rat N-methyl-D-aspartate receptors expressed in human embryonic kidney HEK293 cells are differentially affected by naturally occurring neurosteroid pregnenolone sulfate. We show that responses induced by 1 mM glutamate in NR1-1a/NR2A and NR1-1a/NR2B receptors are potentiated five- to eight-fold more by pregnenolone sulfate than responses of NR1-1a/NR2C and NR1-1a/ NR2D receptors with no differences in the concentration of pregnenolone sulfate that produced 50% potentiation. In addition to potentiation, pregnenolone sulfate also has an inhibitory effect at recombinant N-methyl-D-aspartate receptors, with values of the concentration of pregnenolone sulfate that produces 50% inhibition of NR1/NR2D=NR1/NR2C < NR1/NR2B < NRl/NR2A. In addition, we show that the structure of the extracellular loop between the third and fourth transmembrane domains of the NR2 subunit is critical for both the potentiating and inhibitory effects of pregnenolone sulfate. The modulatory effects of pregnenolone sulfate are consistent with a model in which this neurosteroid acts at two distinct binding sites on the N-methyl-D-aspartate receptor. These data provide insight into the mechanisms by which pregnenolone sulfate and related sulfated neurosteroids modulate activity of N-methyl-D-aspartate receptor channels. (c) 2005 Published by Elsevier Ltd on behalf of IBRO.