Biophysics of Serotonin and the Serotonin1A Receptor

Sarkar, Parijat; Kumar, G. Aditya; Pal, Sreetama; Chattopadhyay, Amitabha

doi:10.1016/b978-0-12-800050-2.00001-2

Cited by 15 publications

(18 citation statements)

References 88 publications

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“…[14][15][16] The serotonin 1A receptor is an important neurotransmitter receptor in the family of serotonin receptors and is implicated in a variety of cognitive, behavioral and developmental functions such as sleep, mood, aggression, anxiety and depression. [17][18][19][20][21][22][23][24] With an overall goal of understanding the mechanistic basis underlying the impaired neuronal function observed in SLOS, we have previously F I G U R E 1 Generating a cellular model of Smith-Lemli-Opitz syndrome. A, Two known pathways of cholesterol biosynthesis are the Kandutsch-Russell and the Bloch pathway.…”

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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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“…Among the subtypes of serotonin receptors, the G protein-coupled serotonin 1A receptor is the most well-studied receptor for various reasons [15,[19][20][21]. One of the major reasons is the early availability of a ligand (8-OH-DPAT) with high selectivity that permits thorough pharmacological, biochemical, and physiological characterization of the serotonin 1A receptor [58,59].…”

Section: Competition Binding Of the Fluorescent Ligands To Serotonin 1a Receptorsmentioning

confidence: 99%

“…Dysfunctional serotonergic signaling has been implicated in the etiology of mental disorders such as schizophrenia, depression, suicidal behavior, infantile autism, and obsessive-compulsive disorder [11][12][13]. Signaling via serotonin is mediated by binding of serotonin to specific receptors on the cell surface, which are pharmacologically categorized into many groups [4,[14][15][16][17]. A majority of serotonin receptors belong to the superfamily of seven transmembrane domain G protein-coupled receptors (GPCRs) [4,16,18].…”

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confidence: 99%

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Environment-Sensitive Fluorescence of 7-Nitrobenz-2-oxa-1,3-diazol-4-yl (NBD)-Labeled Ligands for Serotonin Receptors

et al. 2021

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Serotonin is a neurotransmitter that plays a crucial role in the regulation of several behavioral and cognitive functions by binding to a number of different serotonin receptors present on the cell surface. We report here the synthesis and characterization of several novel fluorescent analogs of serotonin in which the fluorescent NBD (7-nitrobenz-2-oxa-1,3-diazol-4-yl) group is covalently attached to serotonin. The fluorescent ligands compete with the serotonin1A receptor specific radiolabeled agonist for binding to the receptor. Interestingly, these fluorescent ligands display a high environmental sensitivity of their fluorescence. Importantly, the human serotonin1A receptor stably expressed in CHO-K1 cells could be specifically labeled with one of the fluorescent ligands with minimal nonspecific labeling. Interestingly, we show by spectral imaging that the NBD-labeled ligand exhibits a red edge excitation shift (REES) of 29 nm when bound to the receptor, implying that it is localized in a restricted microenvironment. Taken together, our results show that NBD-labeled serotonin analogs offer an attractive fluorescent approach for elucidating the molecular environment of the serotonin binding site in serotonin receptors. In view of the multiple roles played by the serotonergic systems in the central and peripheral nervous systems, these fluorescent ligands would be useful in future studies involving serotonin receptors.

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“…G protein-coupled receptors (GPCRs) are the largest class of receptors in the plasma membrane that transduce extracellular signals to the cellular interior. − GPCRs act as crucial communication hubs on the cell membrane and facilitate a wide array of cellular signaling processes upon binding to a diverse variety of ligands. , As a consequence of the varied range of physiological processes regulated by GPCRs, they are popular drug targets and ∼40% of approved drugs in the current market act on GPCRs . The serotonin 1A receptor − is one of the most comprehensively studied neurotransmitter receptors in the GPCR family. The serotonin 1A receptor mediates a multitude of neurological functions associated with the neurotransmitter serotonin, the endogenous ligand for the receptor.…”

Section: Introductionmentioning

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Cell Cycle Dependent Modulation of Membrane Dipole Potential and Neurotransmitter Receptor Activity: Role of Membrane Cholesterol

Sarkar

Rao

Chattopadhyay

2020

ACS Chem. Neurosci.

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The cell cycle is a sequential multistep process essential for growth and proliferation of cells that make up multicellular organisms. A number of nuclear and cytoplasmic proteins are known to modulate the cell cycle. Yet, the role of lipids, membrane organization, and physical properties in cell cycle progression remains largely elusive. Membrane dipole potential is an important physicochemical property and originates due to the electrostatic potential difference within the membrane because of nonrandom arrangement of amphiphile dipoles and water molecules at the membrane interface. In this work, we explored the modulation of membrane dipole potential in various stages of the cell cycle in CHO-K1 cells. Our results show that membrane dipole potential is highest in the G1 phase relative to S and G2/M phases. This was accompanied by regulation of membrane cholesterol content in the cell cycle. The highest cholesterol content was found in the G1 phase with a considerable reduction in cholesterol in S and G2/M phases. Interestingly, we noted a similarity in the dependence of membrane dipole potential and cholesterol with progress of the cell cycle. In addition, we observed an increase in neutral lipid (which contains esterified cholesterol) content as cells progressed from the G1 to G2/M phase via the S phase of the cell cycle. Importantly, we further observed a cell cycle dependent reduction in ligand binding activity of serotonin1A receptors expressed in CHO-K1 cells. To the best of our knowledge, these results constitute the first report of cell cycle dependent modulation of membrane dipole potential and activity of a neurotransmitter receptor belonging to the G protein-coupled receptor family. We envision that understanding the basis of cell cycle events from a biophysical perspective would result in a deeper appreciation of the cell cycle and its regulation in relation to cellular function.

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Biophysics of Serotonin and the Serotonin1A Receptor

Cited by 15 publications

References 88 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

Environment-Sensitive Fluorescence of 7-Nitrobenz-2-oxa-1,3-diazol-4-yl (NBD)-Labeled Ligands for Serotonin Receptors

Cell Cycle Dependent Modulation of Membrane Dipole Potential and Neurotransmitter Receptor Activity: Role of Membrane Cholesterol

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