Structural Stringency and Optimal Nature of Cholesterol Requirement in the Function of the Serotonin1A Receptor

Sarkar, Parijat; Jafurulla,; Bhowmick, Sukanya; Chattopadhyay, Amitabha

doi:10.1007/s00232-020-00138-x

Cited by 10 publications

(10 citation statements)

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“…In this context, previous work from our laboratory has demonstrated impaired ligand binding, G-protein coupling and cellular signaling by the serotonin 1A receptor under SLOS-like conditions. [25][26][27][28] In this work, we show that the plasma membrane population of serotonin 1A receptors exhibits a considerable reduction in a cellular model of SLOS generated by treating cells with AY 9944. Our results 45,50,51 In addition, our results show that serotonin 1A receptors are trafficked to these compartments upon AY 9944 treatment, indicating an altered trafficking pathway associated with SLOS-mimicking conditions.…”

Section: Discussionmentioning

confidence: 66%

“…shown that functional aspects of the serotonin 1A receptor, such as ligand binding, G-protein coupling and cellular signaling, are affected in SLOS-like conditions. [25][26][27][28] Extensive work over the past decade has highlighted the importance of spatiotemporal organization of GPCRs in their cellular function. [29][30][31] Although GPCRs have been classically considered to be plasma membrane resident signaling hubs, their subcellular localization has emerged as an important feature associated with regulation of their function.…”

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confidence: 99%

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

Sharma

Kumar

Chattopadhyay

2021

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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-Δ 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.

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

Sharma

Kumar

Chattopadhyay

2021

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“…The function of several GPCRs has been shown to be intimately dependent on membrane cholesterol. For example, we have previously shown that the serotonin 1A receptor exhibits sensitivity toward membrane cholesterol in terms of its organization, dynamics, and function (13)(14)(15)(16)(17)(18)(19)(20)22). Such cholesterol dependence of GPCRs could be attributed to structural features of these receptors that could facilitate their preferential association with membrane cholesterol.…”

Section: Discussionmentioning

confidence: 99%

“…The role of membrane cholesterol in the function of several GPCRs has been reported (6)(7)(8)(9)(10). We have previously shown that the serotonin 1A receptor, a representative class A neurotransmitter GPCR (11,12), exhibits sensitivity toward membrane cholesterol in terms of its organization, dynamics, function, and trafficking (13)(14)(15)(16)(17)(18)(19)(20)(21)(22). However, the mechanistic basis underlying the cholesterolsensitive GPCR function remains elusive.…”

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confidence: 99%

A molecular sensor for cholesterol in the human serotonin _1A receptor

et al. 2021

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The function of several G protein–coupled receptors (GPCRs) exhibits cholesterol sensitivity. Cholesterol sensitivity of GPCRs could be attributed to specific sequence and structural features, such as the cholesterol recognition/interaction amino acid consensus (CRAC) motif, that facilitate their cholesterol-receptor interaction. In this work, we explored the molecular basis of cholesterol sensitivity exhibited by the serotonin1A receptor, the most studied GPCR in the context of cholesterol sensitivity, by generating mutants of key residues in CRAC motifs in transmembrane helix 2 (TM2) and TM5 of the receptor. Our results show that a lysine residue (K101) in one of the CRAC motifs is crucial for sensing altered membrane cholesterol levels. Insights from all-atom molecular dynamics simulations showed that cholesterol-sensitive functional states of the serotonin1A receptor are associated with reduced conformational dynamics of extracellular loops of the receptor. These results constitute one of the first reports on the molecular mechanism underlying cholesterol sensitivity of GPCRs.

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“…Receptor-lipid interactions are a cornerstone in receptor biology dictating receptor stability and structural dynamics. Chattopadhyay and co-workers report on the physico-chemical mechanisms underlying the interaction of sterols with GPCRs (Sarkar et al 2020b). They have considered two immediate biosynthetic precursors of cholesterol, 7-dehydrocholesterol (7-DHC) and desmosterol, and showed that GPCR activity is sterol dependent.…”

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Molecular Interplay at the Membrane and Impact on Cellular Physiology

2021

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Structural Stringency and Optimal Nature of Cholesterol Requirement in the Function of the Serotonin1A Receptor

Cited by 10 publications

References 93 publications

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

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

A molecular sensor for cholesterol in the human serotonin _1A receptor

Molecular Interplay at the Membrane and Impact on Cellular Physiology

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Structural Stringency and Optimal Nature of Cholesterol Requirement in the Function of the Serotonin1A Receptor

Cited by 10 publications

References 93 publications

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

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

A molecular sensor for cholesterol in the human serotonin 1A receptor

Molecular Interplay at the Membrane and Impact on Cellular Physiology

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A molecular sensor for cholesterol in the human serotonin _1A receptor