Sarkar Parijat, Chattopadhyay Amitabha
CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007, India.
Academy of Scientific and Innovative Research, Ghaziabad 201 002, India.
ACS Chem Neurosci. 2023 Oct 18;14(20):3855-3868. doi: 10.1021/acschemneuro.3c00472. Epub 2023 Oct 7.
Serotonin receptors are important neurotransmitter receptors in the G protein-coupled receptor (GPCR) family and modulate a variety of neurological, behavioral, and cognitive functions. We recently showed that chronic cholesterol depletion by statins, potent inhibitors of HMG-CoA reductase (the rate-limiting enzyme in cholesterol biosynthesis), leads to polymerization of the actin cytoskeleton that alters lateral diffusion of serotonin receptors. However, cellular signaling by the serotonin receptor under chronic cholesterol depletion remains unexplored. In this work, we explored signaling by the serotonin receptor under statin-treated condition. We show that cAMP signaling by the receptor is reduced upon lovastatin treatment due to reduction in cholesterol as well as polymerization of the actin cytoskeleton. To the best of our knowledge, these results constitute the first report describing the effect of chronic cholesterol depletion on the signaling of a G protein-coupled neuronal receptor. An important message arising from these results is that it is prudent to include the contribution of actin polymerization while analyzing changes in membrane protein function due to chronic cholesterol depletion by statins. Notably, our results show that whereas actin polymerization acts as a negative regulator of cAMP signaling, cholesterol could act as a positive modulator. These results assume significance in view of reports highlighting symptoms of anxiety and depression in humans upon statin administration and the role of serotonin receptors in anxiety and depression. Overall, these results reveal a novel role of actin polymerization induced by chronic cholesterol depletion in modulating GPCR signaling, which could act as a potential therapeutic target.
血清素受体是G蛋白偶联受体（GPCR）家族中重要的神经递质受体，可调节多种神经、行为和认知功能。我们最近发现，他汀类药物（HMG-CoA还原酶的强效抑制剂，HMG-CoA还原酶是胆固醇生物合成中的限速酶）导致的慢性胆固醇耗竭会引发肌动蛋白细胞骨架聚合，进而改变血清素受体的侧向扩散。然而，慢性胆固醇耗竭状态下血清素受体的细胞信号传导仍未得到探索。在这项研究中，我们探究了他汀类药物处理条件下血清素受体的信号传导。我们发现，洛伐他汀处理后，由于胆固醇减少以及肌动蛋白细胞骨架聚合，该受体的cAMP信号传导降低。据我们所知，这些结果构成了第一份描述慢性胆固醇耗竭对G蛋白偶联神经元受体信号传导影响的报告。这些结果传递的一个重要信息是，在分析他汀类药物导致的慢性胆固醇耗竭引起的膜蛋白功能变化时，谨慎考虑肌动蛋白聚合的作用是明智的。值得注意的是，我们的结果表明，虽然肌动蛋白聚合作为cAMP信号传导的负调节因子，但胆固醇可能作为正调节因子。鉴于有报告强调人类服用他汀类药物后出现焦虑和抑郁症状以及血清素受体在焦虑和抑郁中的作用，这些结果具有重要意义。总体而言，这些结果揭示了慢性胆固醇耗竭诱导的肌动蛋白聚合在调节GPCR信号传导中的新作用，这可能成为一个潜在的治疗靶点。
