Sharma, Ashwani ; Kumar, G. Aditya ; Chattopadhyay, Amitabha (2021) Late endosomal/lysosomal accumulation of a neurotransmitter receptor in a cellular model of Smith‐Lemli‐Opitz syndrome Traffic, 22 (10). pp. 332-344. ISSN 1398-9219
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Official URL: http://doi.org/10.1111/tra.12811
Related URL: http://dx.doi.org/10.1111/tra.12811
Abstract
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 serotonin1A 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 serotonin1A 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.
Item Type: | Article |
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Source: | Copyright of this article belongs to John Wiley & Sons, Inc |
ID Code: | 134966 |
Deposited On: | 17 Jan 2023 08:53 |
Last Modified: | 17 Jan 2023 08:53 |
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