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首页> 外文期刊>Neuroscience: An International Journal under the Editorial Direction of IBRO >Activation of the androgen receptor alters the intracellular calcium response to glutamate in primary hippocampal neurons and modulates sarco/endoplasmic reticulum calcium ATPase 2 transcription.
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Activation of the androgen receptor alters the intracellular calcium response to glutamate in primary hippocampal neurons and modulates sarco/endoplasmic reticulum calcium ATPase 2 transcription.

机译：雄激素受体的激活改变了原代海马神经元中谷氨酸对细胞内钙的反应，并调节了肌/内质网钙ATP酶2的转录。

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摘要

Androgens have been shown to have a number of effects on hippocampal function. Although androgen receptors (AR) are found at high levels in hippocampal neurons, the intracellular mechanisms responsible for androgen's actions are unknown. If androgens were capable of altering internal calcium concentration ([Ca(2+)](i)), they could influence a variety of intracellular signaling pathways, maintain neuronal homeostasis and Ca(2+) induced excitotoxicity. In the present study, calcium imaging was used to measure the [Ca(2+)](i) in rat primary hippocampal neurons treated with either the AR agonist dihydrotestosterone (DHT), DHT+flutamide (AR antagonist), flutamide alone, or vehicle for 24 h and subsequently presented with an excitatory glutamate stimulus. In the absence of glutamate stimulation, DHT treatment caused a significant upward shift in baseline [Ca(2+)](i) when compared with neurons from all other groups. Glutamate had a greater effect on [Ca(2+)](i) in DHT-treated neurons and DHT-treated neurons returned to baseline levels significantly faster than all other groups. Cyclopiazonic acid, an inhibitor of sarco/endoplasmic reticulum calcium ATPase (SERCA) had a larger response in DHT-treated neurons compared with controls, suggesting increased Ca(2+) stores in DHT-treated neurons. In all cases the effects of DHT were blocked by treatment with flutamide indicating an AR-mediated mechanism. To determine a possible mechanism by which AR activation could be influencing [Ca(2+)](i), SERCA2 mRNA levels were measured in primary hippocampal neurons. SERCA2 is inserted into the endoplasmic reticulum (ER) membrane and functions to rapidly pump [Ca(2+)](i) into the ER. Following treatment of primary hippocampal neurons with DHT, SERCA2 mRNA was increased, an effect that was blocked in the presence of flutamide. Taken together these results indicate that DHT, working through AR, causes an up-regulation of SERCA2, which increases the sequestering of [Ca(2+)](i) in the endoplasmic reticulum of hippocampal neurons. Such changes may allow the neurons to respond more robustly to a stimulus and recover more quickly following a highly stimulatory challenge.
机译：已显示雄激素对海马功能有许多作用。尽管在海马神经元中发现高水平的雄激素受体（AR），但负责雄激素作用的细胞内机制尚不清楚。如果雄激素能够改变内部钙浓度（[Ca（2 +）]（i）），它们可能会影响多种细胞内信号传导途径，维持神经元稳态和Ca（2+）引起的兴奋性毒性。在本研究中，钙成像用于测量大鼠AR海马激动剂二氢睾丸激素（DHT），DHT +氟他胺（AR拮抗剂），单独使用氟他胺或载体24小时，随后给予兴奋性谷氨酸刺激。在没有谷氨酸刺激的情况下，与所有其他组的神经元相比，DHT治疗引起基线[Ca（2 +）]（i）的显着上移。谷氨酸对DHT处理的神经元中的[Ca（2 +）]（i）具有更大的影响，而DHT处理的神经元返回基线水平的速度明显快于所有其他组。 Cyclopiazonic酸，肌氨酸/内质网钙ATPase（SERCA）的抑制剂与对照相比，在DHT处理的神经元中具有更大的响应，表明在DHT处理的神经元中Ca（2+）存储增加。在所有情况下，通过氟他胺治疗均可阻断DHT的作用，这表明AR介导的机制。为了确定AR激活可能影响[Ca（2 +）]（i）的可能机制，在原代海马神经元中测量了SERCA2 mRNA水平。 SERCA2插入到内质网（ER）膜中，并具有将[Ca（2 +）]（i）迅速泵入ER的功能。用DHT治疗原发性海马神经元后，SERCA2 mRNA升高，在氟他胺的存在下这种作用被阻断。总之，这些结果表明DHT通过AR引起SERCA2的上调，从而增加了海马神经元内质网中[Ca（2 +）]（i）的螯合。这种变化可能使神经元对刺激产生更强烈的反应，并在高度刺激的刺激下更快恢复。

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