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      Glycine and Glycine Receptor Signalling in Non-Neuronal Cells

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          Abstract

          Glycine is an inhibitory neurotransmitter acting mainly in the caudal part of the central nervous system. Besides this neurotransmitter function, glycine has cytoprotective and modulatory effects in different non-neuronal cell types. Modulatory effects were mainly described in immune cells, endothelial cells and macroglial cells, where glycine modulates proliferation, differentiation, migration and cytokine production. Activation of glycine receptors (GlyRs) causes membrane potential changes that in turn modulate calcium flux and downstream effects in these cells. Cytoprotective effects were mainly described in renal cells, hepatocytes and endothelial cells, where glycine protects cells from ischemic cell death. In these cell types, glycine has been suggested to stabilize porous defects that develop in the plasma membranes of ischemic cells, leading to leakage of macromolecules and subsequent cell death. Although there is some evidence linking these effects to the activation of GlyRs, they seem to operate in an entirely different mode from classical neuronal subtypes.

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          Most cited references143

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          Molecular structure and function of the glycine receptor chloride channel.

          The glycine receptor chloride channel (GlyR) is a member of the nicotinic acetylcholine receptor family of ligand-gated ion channels. Functional receptors of this family comprise five subunits and are important targets for neuroactive drugs. The GlyR is best known for mediating inhibitory neurotransmission in the spinal cord and brain stem, although recent evidence suggests it may also have other physiological roles, including excitatory neurotransmission in embryonic neurons. To date, four alpha-subunits (alpha1 to alpha4) and one beta-subunit have been identified. The differential expression of subunits underlies a diversity in GlyR pharmacology. A developmental switch from alpha2 to alpha1beta is completed by around postnatal day 20 in the rat. The beta-subunit is responsible for anchoring GlyRs to the subsynaptic cytoskeleton via the cytoplasmic protein gephyrin. The last few years have seen a surge in interest in these receptors. Consequently, a wealth of information has recently emerged concerning GlyR molecular structure and function. Most of the information has been obtained from homomeric alpha1 GlyRs, with the roles of the other subunits receiving relatively little attention. Heritable mutations to human GlyR genes give rise to a rare neurological disorder, hyperekplexia (or startle disease). Similar syndromes also occur in other species. A rapidly growing list of compounds has been shown to exert potent modulatory effects on this receptor. Since GlyRs are involved in motor reflex circuits of the spinal cord and provide inhibitory synapses onto pain sensory neurons, these agents may provide lead compounds for the development of muscle relaxant and peripheral analgesic drugs.
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            Calcium signaling mechanisms in T lymphocytes.

            Elevation of intracellular free Ca(2+) is one of the key triggering signals for T-cell activation by antigen. A remarkable variety of Ca(2+) signals in T cells, ranging from infrequent spikes to sustained oscillations and plateaus, derives from the interactions of multiple Ca(2+) sources and sinks in the cell. Following engagement of the T cell receptor, intracellular channels (IP3 and ryanodine receptors) release Ca(2+) from intracellular stores, and by depleting the stores trigger prolonged Ca(2+) influx through store-operated Ca(2+) (CRAC) channels in the plasma membrane. The amplitude and dynamics of the Ca(2+) signal are shaped by several mechanisms, including K(+) channels and membrane potential, slow modulation of the plasma membrane Ca(2+)-ATPase, and mitochondria that buffer Ca(2+) and prevent the inactivation of CRAC channels. Ca(2+) signals have a number of downstream targets occurring on multiple time scales. At short times, Ca(2+) signals help to stabilize contacts between T cells and antigen-presenting cells through changes in motility and cytoskeletal reorganization. Over periods of minutes to hours, the amplitude, duration, and kinetic signature of Ca(2+) signals increase the efficiency and specificity of gene activation events. The complexity of Ca(2+) signals contains a wealth of information that may help to instruct lymphocytes to choose between alternate fates in response to antigenic stimulation.
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              GlyR alpha3: an essential target for spinal PGE2-mediated inflammatory pain sensitization.

              Prostaglandin E2 (PGE2) is a crucial mediator of inflammatory pain sensitization. Here, we demonstrate that inhibition of a specific glycine receptor subtype (GlyR alpha3) by PGE2-induced receptor phosphorylation underlies central inflammatory pain sensitization. We show that GlyR alpha3 is distinctly expressed in superficial layers of the spinal cord dorsal horn. Mice deficient in GlyR alpha3 not only lack the inhibition of glycinergic neurotransmission by PGE2 seen in wild-type mice but also show a reduction in pain sensitization induced by spinal PGE2 injection or peripheral inflammation. Thus, GlyR alpha3 may provide a previously unrecognized molecular target in pain therapy.
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                Author and article information

                Journal
                Front Mol Neurosci
                Front. Mol. Neurosci.
                Frontiers in Molecular Neuroscience
                Frontiers Research Foundation
                1662-5099
                13 July 2009
                20 August 2009
                2009
                : 2
                : 9
                Affiliations
                [1] 1simpleInstitute of Biomedical Research, Hasselt University and transnationale Universiteit Limburg Diepenbeek, Belgium
                [2] 2simpleKennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, Charing Cross Campus London, UK
                [3] 3simpleDepartment of Pharmacology, School of Pharmacy, University of London London, UK
                Author notes

                Edited by: Jochen C. Meier, Max Delbrück Center for Molecular Medicine, Germany

                Reviewed by: Luis Aguayo, Universidad de Concepción, Chile; Claudia Eder, University of London, UK

                *Correspondence: Jean-Michel Rigo, Institute of Biomedical Research, Hasselt University and transnationale Universiteit Limburg, Agoralaan, Building C, B-3590 Diepenbeek, Belgium. e-mail: jeanmichel.rigo@ 123456uhasselt.be
                Article
                10.3389/neuro.02.009.2009
                2737430
                19738917
                2a5cb5a6-850d-4a71-b238-554f4c7712d2
                Copyright © 2009 Van den Eynden, SahebAli, Horwood, Carmans, Brône, Hellings, Steels, Harvey and Rigo.

                This is an open-access article subject to an exclusive license agreement between the authors and the Frontiers Research Foundation, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are credited.

                History
                : 24 June 2009
                : 23 July 2009
                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 149, Pages: 12, Words: 11947
                Categories
                Neuroscience
                Review Article

                Neurosciences
                glia,immune cells,cytoprotection,hepatocytes,renal cells,glycine receptor,endothelial cells
                Neurosciences
                glia, immune cells, cytoprotection, hepatocytes, renal cells, glycine receptor, endothelial cells

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