Late endosomal/lysosomal accumulation of a neurotransmitter receptor in a cellular model of Smith-Lemli-Opitz syndrome,Traffic

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Late endosomal/lysosomal accumulation of a neurotransmitter receptor in a cellular model of Smith-Lemli-Opitz syndrome
Traffic ( IF 3.6 ) Pub Date : 2021-08-21 , DOI: 10.1111/tra.12811
Ashwani Sharma _{1,

2} , G Aditya Kumar ₁ , Amitabha Chattopadhyay _{1,

2}

Affiliation

Smith-Lemli-Opitz syndrome (SLOS) is a congenital and developmental malformation syndrome associated with defective cholesterol biosynthesis. It is characterized by accumulation of 7-dehydrocholesterol (the immediate biosynthetic precursor of cholesterol in the Kandutsch-Russell pathway) and an altered cholesterol to total sterol ratio. Because SLOS is associated with neurological malfunction, exploring the function and trafficking of neuronal receptors and their interaction with membrane lipids under these conditions assume significance. In this work, we generated a cellular model of SLOS in HEK-293 cells stably expressing the human serotonin_1A receptor (an important neurotransmitter G-protein coupled receptor) using AY 9944, an inhibitor for the enzyme 3β-hydroxy-steroid-∆⁷-reductase (7-DHCR). Using a quantitative flow cytometry based assay, we show that the plasma membrane population of serotonin_1A receptors was considerably reduced under these conditions without any change in total cellular expression of the receptor. Interestingly, the receptors were trafficked to sterol-enriched LysoTracker positive compartments, which accumulated under these conditions. To the best of our knowledge, our results constitute one of the first reports demonstrating intracellular accumulation and misregulated traffic of a neurotransmitter GPCR in SLOS-like conditions. We believe these results assume relevance in our overall understanding of the molecular basis underlying the functional relevance of neurotransmitter receptors in SLOS.

中文翻译：

Smith-Lemli-Opitz 综合征细胞模型中神经递质受体的晚期内体/溶酶体积累

Smith-Lemli-Opitz 综合征 (SLOS) 是一种与胆固醇生物合成缺陷相关的先天性发育畸形综合征。它的特点是 7-脱氢胆固醇（Kandutsch-Russell 途径中胆固醇的直接生物合成前体）的积累和胆固醇与总甾醇的比例发生改变。由于 SLOS 与神经功能障碍有关，因此探索神经元受体的功能和运输以及它们在这些条件下与膜脂的相互作用具有重要意义。在这项工作中，我们使用 AY 9944（一种酶 3β-羟基类固醇-Δ7 的抑制剂）在 HEK-293 细胞中生成了稳定表达人血清素_{1A受体（一种重要的神经递质 G 蛋白偶联受体）的}^{SLOS细胞模型}-还原酶（7-DHCR）。使用基于定量流式细胞仪的测定，我们表明在这些条件下，血清素_1A受体的质膜群体显着减少，而受体的总细胞表达没有任何变化。有趣的是，受体被运送到富含甾醇的 LysoTracker 阳性隔室，这些隔室在这些条件下积累。据我们所知，我们的结果构成了首批报告之一，证明了在 SLOS 样条件下神经递质 GPCR 的细胞内积累和错误调节的交通。我们相信这些结果与我们对 SLOS 中神经递质受体功能相关性的分子基础的整体理解相关。

更新日期：2021-08-27

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