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      Choline Is an Intracellular Messenger Linking Extracellular Stimuli to IP 3-Evoked Ca 2+ Signals through Sigma-1 Receptors

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          Summary

          Sigma-1 receptors (Sig-1Rs) are integral ER membrane proteins. They bind diverse ligands, including psychoactive drugs, and regulate many signaling proteins, including the inositol 1,4,5-trisphosphate receptors (IP 3Rs) that release Ca 2+ from the ER. The endogenous ligands of Sig-1Rs are unknown. Phospholipase D (PLD) cleaves phosphatidylcholine to choline and phosphatidic acid (PA), with PA assumed to mediate all downstream signaling. We show that choline is also an intracellular messenger. Choline binds to Sig-1Rs, it mimics other Sig-1R agonists by potentiating Ca 2+ signals evoked by IP 3Rs, and it is deactivated by metabolism. Receptors, by stimulating PLC and PLD, deliver two signals to IP 3Rs: IP 3 activates IP 3Rs, and choline potentiates their activity through Sig-1Rs. Choline is also produced at synapses by degradation of acetylcholine. Choline uptake by transporters activates Sig-1Rs and potentiates Ca 2+ signals. We conclude that choline is an endogenous agonist of Sig-1Rs linking extracellular stimuli, and perhaps synaptic activity, to Ca 2+ signals.

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          Highlights

          • Choline, but not its metabolites, binds to Sigma-1 receptors

          • Choline potentiates IP 3-evoked Ca 2+ release by activating Sigma-1 receptors

          • Bradykinin stimulates Ca 2+ release by stimulating formation of IP 3 and choline

          • Choline uptake by a specific transporter potentiates IP 3-evoked Ca 2+ release

          Abstract

          Sigma-1 receptors respond to diverse stimuli and regulate many signaling proteins. Brailoiu et al. show that choline is an endogenous agonist of Sigma-1 receptors. Choline links receptors and cholinergic synaptic activity, through Sigma-1 receptors, to enhanced Ca 2+ release through IP 3 receptors.

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          Most cited references40

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          Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior.

          Acetylcholine in the brain alters neuronal excitability, influences synaptic transmission, induces synaptic plasticity, and coordinates firing of groups of neurons. As a result, it changes the state of neuronal networks throughout the brain and modifies their response to internal and external inputs: the classical role of a neuromodulator. Here, we identify actions of cholinergic signaling on cellular and synaptic properties of neurons in several brain areas and discuss consequences of this signaling on behaviors related to drug abuse, attention, food intake, and affect. The diverse effects of acetylcholine depend on site of release, receptor subtypes, and target neuronal population; however, a common theme is that acetylcholine potentiates behaviors that are adaptive to environmental stimuli and decreases responses to ongoing stimuli that do not require immediate action. The ability of acetylcholine to coordinate the response of neuronal networks in many brain areas makes cholinergic modulation an essential mechanism underlying complex behaviors. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Crystal structure of the human σ1 receptor.

            The human σ1 receptor is an enigmatic endoplasmic-reticulum-resident transmembrane protein implicated in a variety of disorders including depression, drug addiction, and neuropathic pain. Recently, an additional connection to amyotrophic lateral sclerosis has emerged from studies of human genetics and mouse models. Unlike many transmembrane receptors that belong to large, extensively studied families such as G-protein-coupled receptors or ligand-gated ion channels, the σ1 receptor is an evolutionary isolate with no discernible similarity to any other human protein. Despite its increasingly clear importance in human physiology and disease, the molecular architecture of the σ1 receptor and its regulation by drug-like compounds remain poorly defined. Here we report crystal structures of the human σ1 receptor in complex with two chemically divergent ligands, PD144418 and 4-IBP. The structures reveal a trimeric architecture with a single transmembrane domain in each protomer. The carboxy-terminal domain of the receptor shows an extensive flat, hydrophobic membrane-proximal surface, suggesting an intimate association with the cytosolic surface of the endoplasmic reticulum membrane in cells. This domain includes a cupin-like β-barrel with the ligand-binding site buried at its centre. This large, hydrophobic ligand-binding cavity shows remarkable plasticity in ligand recognition, binding the two ligands in similar positions despite dissimilar chemical structures. Taken together, these results reveal the overall architecture, oligomerization state, and molecular basis for ligand recognition by this important but poorly understood protein.
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              Choline metabolism provides novel insights into nonalcoholic fatty liver disease and its progression.

              Choline is an essential nutrient and the liver is a central organ responsible for choline metabolism. Hepatosteatosis and liver cell death occur when humans are deprived of choline. In the last few years, there have been significant advances in our understanding of the mechanisms that influence choline requirements in humans and in our understanding of choline's effects on liver function. These advances are useful in elucidating why nonalcoholic fatty liver disease (NAFLD) occurs and progresses sometimes to hepatocarcinogenesis. Humans eating low-choline diets develop fatty liver and liver damage. This dietary requirement for choline is modulated by estrogen and by single-nucleotide polymorphisms in specific genes of choline and folate metabolism. The spectrum of choline's effects on liver range from steatosis to development of hepatocarcinomas, and several mechanisms for these effects have been identified. They include abnormal phospholipid synthesis, defects in lipoprotein secretion, oxidative damage caused by mitochondrial dysfunction, and endoplasmic reticulum stress. Furthermore, the hepatic steatosis phenotype can be characterized more fully via metabolomic signatures and is influenced by the gut microbiome. Importantly, the intricate connection between liver function, one-carbon metabolism, and energy metabolism is just beginning to be elucidated. Choline influences liver function, and the dietary requirement for this nutrient varies depending on an individual's genotype and estrogen status. Understanding these individual differences is important for gastroenterologists seeking to understand why some individuals develop NAFLD and others do not, and why some patients tolerate total parenteral nutrition and others develop liver dysfunction.
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                Author and article information

                Contributors
                Journal
                Cell Rep
                Cell Rep
                Cell Reports
                Cell Press
                2211-1247
                08 January 2019
                08 January 2019
                08 January 2019
                : 26
                : 2
                : 330-337.e4
                Affiliations
                [1 ]Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
                [2 ]Department of Pharmacology, Tennis Court Road, Cambridge CB2 1PD, UK
                [3 ]Department of Pharmaceutical Sciences, Jefferson College of Pharmacy, Thomas Jefferson University, Philadelphia, PA 19107, USA
                [4 ]Department of Pharmaceutical Sciences, Temple University School of Pharmacy, Philadelphia, PA 19140, USA
                Author notes
                []Corresponding author ebrailou@ 123456temple.edu
                [∗∗ ]Corresponding author cwt1000@ 123456cam.ac.uk
                [5]

                Present address: Centre for Brain Development and Repair, Institute for Stem Cell Biology and Regenerative Medicine, Bengaluru, KA 560065, India

                [6]

                These authors contributed equally

                [7]

                Lead Contact

                Article
                S2211-1247(18)31981-8
                10.1016/j.celrep.2018.12.051
                6326163
                30625315
                fa1a90a7-e3d5-4c0b-8fdb-2c028e994162
                © 2018 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 31 July 2018
                : 11 October 2018
                : 11 December 2018
                Categories
                Article

                Cell biology
                bradykinin,ca2+,choline,g-protein-coupled receptor,ip3 receptor,intracellular messenger,neurotransmitter,phospholipase c,phospholipase d,sigma-1 receptor

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