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      Dopamine in Health and Disease: Much More Than a Neurotransmitter

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          Abstract

          Dopamine is derived from an amino acid, phenylalanine, which must be obtained through the diet. Dopamine, known primarily to be a neurotransmitter involved in almost any higher executive action, acts through five types of G-protein-coupled receptors. Dopamine has been studied extensively for its neuronal handling, synaptic actions, and in relation to Parkinson’s disease. However, dopamine receptors can be found extra-synaptically and, in addition, they are not only expressed in neurons, but in many types of mammalian cells, inside and outside the central nervous system (CNS). Recent studies show a dopamine link between the gut and the CNS; the mechanisms are unknown, but they probably require cells to act as mediators and the involvement of the immune system. In fact, dopamine receptors are expressed in almost any cell of the immune system where dopamine regulates various processes, such as antigen presentation, T-cell activation, and inflammation. This likely immune cell-mediated linkage opens up a new perspective for the use of dopamine-related drugs, i.e., agonist–antagonist–allosteric modulators of dopamine receptors, in a variety of diseases.

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          Neurotransmitter modulation by the gut microbiota

          The gut microbiota – the trillions of bacteria that reside within the gastrointestinal tract – has been found to not only be an essential component immune and metabolic health, but also seems to influence development and diseases of the enteric and central nervous system, including motility disorders, behavioral disorders, neurodegenerative disease, cerebrovascular accidents, and neuroimmune-mediated disorders. By leveraging animal models, several different pathways of communication have been identified along the “gut-brain-axis” including those driven by the immune system, the vagus nerve, or by modulation of neuroactive compounds by the microbiota. Of the latter, bacteria have been shown to produce and/or consume a wide range of mammalian neurotransmitters, including dopamine, norepinephrine, serotonin, or gamma-aminobutyric acid (GABA). Accumulating evidence in animals suggests that manipulation of these neurotransmitters by bacteria may have an impact in host physiology, and preliminary human studies are showing that microbiota-based interventions can also alter neurotransmitter levels. Nonetheless, substantially more work is required to determine whether microbiota-mediated manipulation of human neurotransmission has any physiological implications, and if so, how it may be leveraged therapeutically. In this review this exciting route of communication along the gut-brain-axis, and accompanying data, are discussed.
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            The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system.

            The gastrointestinal tract is covered by mucus that has different properties in the stomach, small intestine, and colon. The large highly glycosylated gel-forming mucins MUC2 and MUC5AC are the major components of the mucus in the intestine and stomach, respectively. In the small intestine, mucus limits the number of bacteria that can reach the epithelium and the Peyer's patches. In the large intestine, the inner mucus layer separates the commensal bacteria from the host epithelium. The outer colonic mucus layer is the natural habitat for the commensal bacteria. The intestinal goblet cells secrete not only the MUC2 mucin but also a number of typical mucus components: CLCA1, FCGBP, AGR2, ZG16, and TFF3. The goblet cells have recently been shown to have a novel gate-keeping role for the presentation of oral antigens to the immune system. Goblet cells deliver small intestinal luminal material to the lamina propria dendritic cells of the tolerogenic CD103(+) type. In addition to the gel-forming mucins, the transmembrane mucins MUC3, MUC12, and MUC17 form the enterocyte glycocalyx that can reach about a micrometer out from the brush border. The MUC17 mucin can shuttle from a surface to an intracellular vesicle localization, suggesting that enterocytes might control and report epithelial microbial challenge. There is communication not only from the epithelial cells to the immune system but also in the opposite direction. One example of this is IL10 that can affect and improve the properties of the inner colonic mucus layer. The mucus and epithelial cells of the gastrointestinal tract are the primary gate keepers and controllers of bacterial interactions with the host immune system, but our understanding of this relationship is still in its infancy. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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              THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein‐coupled receptors

              The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (http://www.guidetopharmacology.org/), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14748. G protein‐coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

                Author and article information

                Journal
                Biomedicines
                Biomedicines
                biomedicines
                Biomedicines
                MDPI
                2227-9059
                22 January 2021
                February 2021
                : 9
                : 2
                : 109
                Affiliations
                [1 ]Neurodegenerative Diseases, CiberNed. Network Research Center, Spanish National Health Institute Carlos III, Valderrebollo 5, 28031 Madrid, Spain; g.navarro@ 123456ub.edu
                [2 ]Department of Biochemistry and Molecular Biomedicine, University of Barcelona, 08028 Barcelona, Spain
                [3 ]Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Science, University of Barcelona, 08028 Barcelona, Spain
                Author notes
                [†]

                Current address: RG Neuroplasticity, Leibniz Institute for Neurobiology 39118, Germany.

                Author information
                https://orcid.org/0000-0003-2549-4919
                https://orcid.org/0000-0003-4654-0873
                Article
                biomedicines-09-00109
                10.3390/biomedicines9020109
                7911410
                33499192
                d729dbda-3600-4a29-b075-d6ae26ddb117
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 03 January 2021
                : 18 January 2021
                Categories
                Review

                microbiota,intestinal flora,parkinson’s disease,immune system,drug development,receptor heteromers,g protein-coupled receptors,l-dopa,inflammation,t-cell activation

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