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      GABA is an effective immunomodulatory molecule

      review-article
      , ,
      Amino Acids
      Springer Vienna
      GABA, GABA-A, Neurotransmitter, Immunomodulation, Autoimmune disease, Immune cells

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          Abstract

          In recent years, it has become clear that there is an extensive cross-talk between the nervous and the immune system. Somewhat surprisingly, the immune cells themselves do express components of the neuronal neurotransmitters systems. What role the neurotransmitters, their ion channels, receptors and transporters have in immune function and regulation is an emerging field of study. Several recent studies have shown that the immune system is capable of synthesizing and releasing the classical neurotransmitter GABA (γ-aminobutyric acid). GABA has a number of effects on the immune cells such as activation or suppression of cytokine secretion, modification of cell proliferation and GABA can even affect migration of the cells. The immune cells encounter GABA when released by the immune cells themselves or when the immune cells enter the brain. In addition, GABA can also be found in tissues like the lymph nodes, the islets of Langerhans and GABA is in high enough concentration in blood to activate, e.g., GABA-A channels. GABA appears to have a role in autoimmune diseases like multiple sclerosis, type 1 diabetes, and rheumatoid arthritis and may modulate the immune response to infections. In the near future, it will be important to work out what specific effects GABA has on the function of the different types of immune cells and determine the underlying mechanisms. In this review, we discuss some of the recent findings revealing the role of GABA as an immunomodulator.

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          Most cited references42

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          GABA A receptors: subtypes provide diversity of function and pharmacology.

          This mini-review attempts to update experimental evidence on the existence of GABA(A) receptor pharmacological subtypes and to produce a list of those native receptors that exist. GABA(A) receptors are chloride channels that mediate inhibitory neurotransmission. They are members of the Cys-loop pentameric ligand-gated ion channel (LGIC) superfamily and share structural and functional homology with other members of that family. They are assembled from a family of 19 homologous subunit gene products and form numerous receptor subtypes with properties that depend upon subunit composition, mostly hetero-oligomeric. These vary in their regulation and developmental expression, and importantly, in brain regional, cellular, and subcellular localization, and thus their role in brain circuits and behaviors. We propose several criteria for including a receptor hetero-oligomeric subtype candidate on a list of native subtypes, and a working GABA(A) receptor list. These criteria can be applied to all the members of the LGIC superfamily. The list is divided into three categories of native receptor subtypes: "Identified", "Existence with High Probability", and "Tentative", and currently includes 26 members, but will undoubtedly grow, with future information. This list was first presented by Olsen & Sieghart (in press).
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            Is Open Access

            Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes

            The risk determinants of type 1 diabetes, initiators of autoimmune response, mechanisms regulating progress toward β cell failure, and factors determining time of presentation of clinical diabetes are poorly understood. We investigated changes in the serum metabolome prospectively in children who later progressed to type 1 diabetes. Serum metabolite profiles were compared between sample series drawn from 56 children who progressed to type 1 diabetes and 73 controls who remained nondiabetic and permanently autoantibody negative. Individuals who developed diabetes had reduced serum levels of succinic acid and phosphatidylcholine (PC) at birth, reduced levels of triglycerides and antioxidant ether phospholipids throughout the follow up, and increased levels of proinflammatory lysoPCs several months before seroconversion to autoantibody positivity. The lipid changes were not attributable to HLA-associated genetic risk. The appearance of insulin and glutamic acid decarboxylase autoantibodies was preceded by diminished ketoleucine and elevated glutamic acid. The metabolic profile was partially normalized after the seroconversion. Autoimmunity may thus be a relatively late response to the early metabolic disturbances. Recognition of these preautoimmune alterations may aid in studies of disease pathogenesis and may open a time window for novel type 1 diabetes prevention strategies.
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              Inhibitory role for GABA in autoimmune inflammation.

              GABA, the principal inhibitory neurotransmitter in the adult brain, has a parallel inhibitory role in the immune system. We demonstrate that immune cells synthesize GABA and have the machinery for GABA catabolism. Antigen-presenting cells (APCs) express functional GABA receptors and respond electrophysiologically to GABA. Thus, the immune system harbors all of the necessary constituents for GABA signaling, and GABA itself may function as a paracrine or autocrine factor. These observations led us to ask further whether manipulation of the GABA pathway influences an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). Increasing GABAergic activity ameliorates ongoing paralysis in EAE via inhibition of inflammation. GABAergic agents act directly on APCs, decreasing MAPK signals and diminishing subsequent adaptive inflammatory responses to myelin proteins.
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                Author and article information

                Contributors
                +46-184714622 , bryndis.birnir@neuro.uu.se , http://www.neuro.uu.se/forskning/forskargrupp.html&id=56
                Journal
                Amino Acids
                Amino Acids
                Amino Acids
                Springer Vienna (Vienna )
                0939-4451
                1438-2199
                13 December 2011
                13 December 2011
                July 2013
                : 45
                : 1
                : 87-94
                Affiliations
                Department of Neuroscience, Molecular Physiology and Neuroscience, Uppsala University, BMC, BOX 593, 75124 Uppsala, Sweden
                Article
                1193
                10.1007/s00726-011-1193-7
                3680704
                22160261
                b2b036ac-7a37-45fe-b109-e814238af6c7
                © The Author(s) 2011
                History
                : 2 August 2011
                : 30 November 2011
                Categories
                Invited Review
                Custom metadata
                © Springer-Verlag Wien 2013

                Genetics
                gaba,gaba-a,neurotransmitter,immunomodulation,autoimmune disease,immune cells
                Genetics
                gaba, gaba-a, neurotransmitter, immunomodulation, autoimmune disease, immune cells

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