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首页> 外文期刊>Glia >Isoform-Selective Regulation of Glycogen Phosphorylase by Energy Deprivation and Phosphorylation in Astrocytes
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Isoform-Selective Regulation of Glycogen Phosphorylase by Energy Deprivation and Phosphorylation in Astrocytes

机译：星形胶质细胞能量缺乏和磷酸化对糖原磷酸化酶的同工型选择性调节

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Glycogen phosphorylase (GP) is activated to degrade glycogen in response to different stimuli, to support both the astrocyte's own metabolic demand and the metabolic needs of neurons. The regulatory mechanism allowing such a glycogenolytic response to distinct triggers remains incompletely understood. In the present study, we used siRNA-mediated differential knockdown of the two isoforms of GP expressed in astrocytes, muscle isoform (GPMM), and brain isoform (GPBB), to analyze isoform-specific regulatory characteristics in a cellular setting. Subsequently, we tested the response of each isoform to phosphorylation, triggered by incubation with norepinephrine (NE), and to AMP, increased by glucose deprivation in cells in which expression of one GP isoform had been silenced. Successful knockdown was demonstrated on the protein level by Western blot, and on a functional level by determination of glycogen content showing an increase in glycogen levels following knockdown of either GPMM or GPBB. NE triggered glycogenolysis within 15 min in control cells and after GPBB knockdown. However, astrocytes in which expression of GPMM had been silenced showed a delay in response to NE, with glycogen levels significantly reduced only after 60 min. In contrast, allosteric activation of GP by AMP, induced by glucose deprivation, seemed to mainly affect GPBB, as only knockdown of GPBB, but not of GPMM, delayed the glycogenolytic response to glucose deprivation. Our results indicate that the two GP isoforms expressed in astrocytes respond to different physiological triggers, therefore conferring distinct metabolic functions of brain glycogen. GLIA 2015;63:154-162
机译：糖原磷酸化酶（GP）被激活以响应不同的刺激降解糖原，从而支持星形胶质细胞自身的代谢需求和神经元的代谢需求。尚不完全了解允许这种糖原分解反应对不同触发因素的调节机制。在本研究中，我们使用了siRNA介导的星形胶质细胞表达的两种同工型GP的异型敲除，肌肉同工型（GPMM）和脑同工型（GPBB），以分析细胞环境中的同工型特异性调控特性。随后，我们测试了每种异型对去甲肾上腺素（NE）孵育触发的磷酸化的响应，以及对其中一种GP异型表达已被沉默的葡萄糖剥夺增加的AMP的响应。通过蛋白质印迹法证明了蛋白水平上的成功敲除，通过糖原含量的测定证实了功能上的敲除，表明在敲除GPMM或GPBB后糖原含量增加。 NE在对照组细胞中和GPBB敲除后15分钟内触发糖原分解。但是，其中GPMM表达已被沉默的星形胶质细胞对NE的反应有所延迟，糖原水平仅在60分钟后才显着降低。相反，由葡萄糖剥夺引起的AMP对GP的变构活化似乎主要影响GPBB，因为只有GPBB的敲​​低，而不是GPMM才延迟了对葡萄糖剥夺的糖原分解反应。我们的结果表明，星形胶质细胞中表达的两个GP同工型响应不同的生理触发，因此赋予脑糖原不同的代谢功能。 GLIA 2015; 63：154-162

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