The neuroactive steroid pregnenolone sulfate stimulates the release of gonadotropin-releasing hormone from GT1-7 hypothalamic neurons, through N-methyl-D-aspartate receptors
The neuroactive steroid pregnenolone sulfate stimulates the release of gonadotropin-releasing hormone from GT1-7 hypothalamic neurons, through N-methyl-D-aspartate receptors
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DOI：
10.1210/en.2005-1191
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发表时间：
2006-06-01
期刊：
影响因子：
4.8
通讯作者：
Schumacher, Michael
中科院分区：
文献类型：
--
作者：
El-Etr, Martine;Akwa, Yvette;Schumacher, Michael
永生化的下丘脑GT 1 -7神经元是研究GnRH分泌控制的良好模型系统。使用这些细胞，我们观察到，神经活性类固醇，硫酸双烯醇酮（PREGS），能够通过N-甲基-D-天冬氨酸（NMDA）受体以剂量依赖性方式刺激GnRH的释放，因为它的作用完全被特定的NMDA受体拮抗剂和镁阻断。GT 1 -7神经元表达各种小鼠NMDA受体亚基（zeta、1、NR 23、NR 24和NR 22，对应于NR 1、NR 2C、NR 2D和NR 2B大鼠亚基）的mRNA，并在外源性谷氨酸或NMDA存在下孵育时增加其GnRH的自发释放。此外，我们发现，这些神经元能够释放和合成谷氨酸，证明了谷氨酸的存在下积累的神经元的定义的孵育培养基中，在实验和表达的mRNA编码的囊泡谷氨酸转运蛋白2，一个特定的标记物的谷氨酸能神经元。PREGS对谷氨酸诱导的GnRH分泌的增强作用与类固醇作为NMDA受体的正变构调节剂的作用一致。总之，这些结果指出了一种新的机制，神经活性类固醇PREGS可能会加强GnRH神经元的自分泌兴奋回路。
Immortalized hypothalamic GT1-7 neurons represent a good model system to investigate the control of GnRH secretion. Using these cells, we observed that the neuroactive steroid, pregnenolone sulfate ( PREGS), is able to stimulate the release of GnRH in a dose-dependent manner through N-methyl-D-aspartate ( NMDA) receptors, because its action is completely blocked by a specific NMDA receptor antagonist and magnesium. GT1-7 neurons express mRNAs for various mouse NMDA receptor subunits (zeta, 1, epsilon 3, epsilon 4, and epsilon 2, corresponding to the NR1, NR2C, NR2D, and NR2B rat subunits) and increase their spontaneous release of GnRH when incubated in the presence of exogenous glutamate or NMDA. In addition, we found that these neurons are able to release and synthesize glutamate, as demonstrated by the presence of glutamate accumulated in the defined incubation medium of the neurons, during the experiment and the expression of mRNA coding for vesicular glutamate transporter 2, a specific marker of glutamatergic neurons. The potentiating effect of PREGS on the secretion of GnRH induced by glutamate is consistent with the role of the steroid as a positive allosteric modulator of NMDA receptors. Together these results point to a novel mechanism by which the neuroactive steroid PREGS may potentiate an autocrine excitatory loop in GnRH neurons.