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The Amino Acid Transporters of the Glutamate/GABA-Glutamine Cycle and Their Impact on Insulin and Glucagon Secretion

1,2,*, 3,4

Frontiers in Endocrinology

Frontiers Media S.A.

GABA, glutamate, glutamine, insulin, SAT2, Slc38a2, Slc38a3, SN1

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      Abstract

      Intercellular communication is pivotal in optimizing and synchronizing cellular responses to keep homeostasis and to respond adequately to external stimuli. In the central nervous system (CNS), glutamatergic and GABAergic signals are postulated to be dependent on the glutamate/GABA-glutamine cycle for vesicular loading of neurotransmitters, for inactivating the signal and for the replenishment of the neurotransmitters. Islets of Langerhans release the hormones insulin and glucagon, but share similarities with CNS cells in for example transcriptional control of development and differentiation, and chromatin methylation. Interestingly, CNS proteins involved in secretion of the neurotransmitters and emitting their responses as well as the regulation of these processes, are also found in islet cells. Moreover, high levels of glutamate, GABA, and glutamine and their respective vesicular and plasma membrane transporters have been shown in the islet cells and there is emerging support for these amino acids and their transporters playing important roles in the maturation and secretion of insulin and glucagon. In this review, we will discuss the feasibility of recent data in the field in relation to the biophysical properties of the transporters (Slc1, Slc17, Slc32, and Slc38) and physiology of hormone secretion in islets of Langerhans.

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      Most cited references 90

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      The expression of vesicular glutamate transporters defines two classes of excitatory synapse.

      The quantal release of glutamate depends on its transport into synaptic vesicles. Recent work has shown that a protein previously implicated in the uptake of inorganic phosphate across the plasma membrane catalyzes glutamate uptake by synaptic vesicles. However, only a subset of glutamate neurons expresses this vesicular glutamate transporter (VGLUT1). We now report that excitatory neurons lacking VGLUT1 express a closely related protein that has also been implicated in phosphate transport. Like VGLUT1, this protein localizes to synaptic vesicles and functions as a vesicular glutamate transporter (VGLUT2). The complementary expression of VGLUT1 and 2 defines two distinct classes of excitatory synapse.
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        Identification and characterization of the vesicular GABA transporter.

        Synaptic transmission involves the regulated exocytosis of vesicles filled with neurotransmitter. Classical transmitters are synthesized in the cytoplasm, and so must be transported into synaptic vesicles. Although the vesicular transporters for monoamines and acetylcholine have been identified, the proteins responsible for packaging the primary inhibitory and excitatory transmitters, gamma-aminobutyric acid (GABA) and glutamate remain unknown. Studies in the nematode Caenorhabditis elegans have implicated the gene unc-47 in the release of GABA. Here we show that the sequence of unc-47 predicts a protein with ten transmembrane domains, that the gene is expressed by GABA neurons, and that the protein colocalizes with synaptic vesicles. Further, a rat homologue of unc-47 is expressed by central GABA neurons and confers vesicular GABA transport in transfected cells with kinetics and substrate specificity similar to those previously reported for synaptic vesicles from the brain. Comparison of this vesicular GABA transporter (VGAT) with a vesicular transporter for monoamines shows that there are differences in the bioenergetic dependence of transport, and these presumably account for the differences in structure. Thus VGAT is the first of a new family of neurotransmitter transporters.
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          The vesicular GABA transporter, VGAT, localizes to synaptic vesicles in sets of glycinergic as well as GABAergic neurons.

          A transporter thought to mediate accumulation of GABA into synaptic vesicles has recently been cloned (McIntire et al., 1997). This vesicular GABA transporter (VGAT), the first vesicular amino acid transporter to be molecularly identified, differs in structure from previously cloned vesicular neurotransmitter transporters and defines a novel gene family. Here we use antibodies specific for N- and C-terminal epitopes of VGAT to localize the protein in the rat CNS. VGAT is highly concentrated in the nerve endings of GABAergic neurons in the brain and spinal cord but also in glycinergic nerve endings. In contrast, hippocampal mossy fiber boutons, which although glutamatergic are known to contain GABA, lack VGAT immunoreactivity. Post-embedding immunogold quantification shows that the protein specifically associates with synaptic vesicles. Triple labeling for VGAT, GABA, and glycine in the lateral oliva superior revealed a higher expression of VGAT in nerve endings rich in GABA, with or without glycine, than in others rich in glycine only. Although the great majority of nerve terminals containing GABA or glycine are immunopositive for VGAT, subpopulations of nerve endings rich in GABA or glycine appear to lack the protein. Additional vesicular transporters or alternative modes of release may therefore contribute to the inhibitory neurotransmission mediated by these two amino acids.
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            Author and article information

            Affiliations
            1Institute for Medical Informatics, Oslo University Hospital, Oslo, Norway
            2Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway
            3Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
            4The Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway
            Author notes

            Edited by: Leif Hertz, China Medical University, China

            Reviewed by: Leif Hertz, China Medical University, China; Michael Byrne Robinson, University of Pennsylvania, USA

            *Correspondence: Monica Jenstad, Institute for Medical Informatics, Oslo University Hospital, Radiumhospitalet, PO Box 4953 Nydalen, Oslo NO-0424, Norway e-mail: mjenstad@123456gmail.com

            This article was submitted to Cellular Endocrinology, a section of the journal Frontiers in Endocrinology.

            Contributors
            URI : http://frontiersin.org/people/u/8585
            Journal
            Front Endocrinol (Lausanne)
            Front Endocrinol (Lausanne)
            Front. Endocrinol.
            Frontiers in Endocrinology
            Frontiers Media S.A.
            1664-2392
            01 November 2013
            31 December 2013
            2013
            : 4
            3876026
            10.3389/fendo.2013.00199
            Copyright © 2013 Jenstad and Chaudhry.

            This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

            Counts
            Figures: 2, Tables: 0, Equations: 0, References: 90, Pages: 8, Words: 6925
            Categories
            Endocrinology
            Mini Review

            Endocrinology & Diabetes

            sat2, glutamine, glutamate, sn1, slc38a3, slc38a2, insulin, gaba

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