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首页> 外文期刊>Biochemistry >Chronic Cholesterol Depletion Using Statin Impairs the Function and Dynamics of Human Serotonin_(1A) Receptors
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Chronic Cholesterol Depletion Using Statin Impairs the Function and Dynamics of Human Serotonin_(1A) Receptors

机译:使用他汀类药物的慢性胆固醇消耗会破坏人血清素_(1A)受体的功能和动力学。

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摘要

Statins are potent inhibitors of HMG-CoA reductase, the key rate-limiting enzyme in cholesterol biosynthesis, and are some of the best selling drugs globally. We have explored the effect of chronic cholesterol depletion induced by mevastatin on the function of human serotoniniA receptors expressed in CHO cells. An advantage with statins is that cholesterol depletion is chronic which mimics physiological conditions. Our results show a significant reduction in the level of specific ligand binding and G-protein coupling to serolonin_(1A) receptors upon chronic cholesterol depletion, although the membrane receptor level is not reduced at all. Interestingly, replenishment of mevastatin-treated cells with cholesterol resulted in the recovery of specific ligand binding and 0-protein coupling. Treatment of cells expressing serotonin IA receptors with mevastatin led to a decrease in the diffusion coefficient and an increase in the mobile fraction of the receptor, as determined by fluorescence recovery after photobleaching measurements. To the best of our knowledge, these results constitute the first report describing the effect of chronic cholesterol depletion on the organization and function of a G-protein-coupled neuronal receptor. Our results assume significance in view of recent reports highlighting the symptoms of anxiety and depression in humans upon statin administration, and the role of serotonin_(1A) receptors in anxiety and depression.
机译:他汀类药物是HMG-CoA还原酶的有效抑制剂,HMG-CoA还原酶是胆固醇生物合成中的关键限速酶,并且是全球范围内最畅销的药物。我们已经研究了美伐他汀诱导的慢性胆固醇耗竭对在CHO细胞中表达的人类血清素A受体功能的影响。他汀类药物的一个优点是胆固醇的消耗是慢性的,可以模拟生理状况。我们的研究结果显示,虽然胆固醇受体的水平并未降低,但在慢性胆固醇耗尽后,特异性配体结合和G蛋白偶联至serolonin_(1A)受体的水平显着降低。有趣的是,用胆固醇补充美伐他汀处理的细胞可导致特异性配体结合和0蛋白偶联的恢复。用美伐他汀处理表达5-羟色胺IA受体的细胞会导致扩散系数降低,受体的可移动分数增加,这是通过光漂白测量后的荧光恢复来确定的。据我们所知,这些结果构成了描述慢性胆固醇耗竭对G蛋白偶联神经元受体组织和功能的影响的第一份报告。鉴于最近有报道强调了他汀类药物给药后人的焦虑和抑郁症状,以及血清素(1A)受体在焦虑和抑郁中的作用,因此我们的结果具有重要意义。

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