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Protein kinase C-mediated phosphorylation of a single serine residue on the rat glial glutamine transporter SN1 governs its membrane trafficking.
Nissen-Meyer LS
,
Popescu MC
,
Hamdani el H
,
Chaudhry FA
.
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Molecular mechanisms involved in the replenishment of the fast neurotransmitters glutamate and GABA are poorly understood. Glutamine sustains their generation. However, glutamine formation from the recycled transmitters is confined to glial processes and requires facilitators for its translocation across the glial and neuronal membranes. Indeed, glial processes are enriched with the system N transporter SN1 (Slc38a3), which, by bidirectional transport, maintains steady extracellular glutamine levels and thereby furnishes neurons with the primary precursor for fast neurotransmitters. We now demonstrate that SN1 is phosphorylated by protein kinase Cα (PKCα) and PKCγ. Electrophysiological characterization shows that phosphorylation reduces V(max) dramatically, whereas no significant effects are seen on the K(m). Phosphorylation occurs specifically at a single serine residue (S52) in the N-terminal rat (Rattus norvegicus) SN1 and results in sequestration of the protein into intracellular reservoirs. Prolonged activation of PKC results in partial degradation of SN1. These results provide the first demonstration of phosphorylation of SN1 and regulation of its activity at the plasma membrane. Interestingly, membrane trafficking of SN1 resembles that of the glutamate transporter GLT and the glutamate-aspartate transporter GLAST: it involves the same PKC isoforms and occurs in the same glial processes. This suggests that the glutamate/GABA-glutamine cycle may be modified at two key points by similar signaling events and unmasks a prominent role for PKC-dependent phosphorylation. Our data suggest that extracellular glutamine levels may be fine-tuned by dynamic regulation of glial SN1 activity, which may impact on transmitter generation, contribute to defining quantal size, and have profound effects on synaptic plasticity.
Acevedo-Duncan,
Aloe-emodin modulates PKC isozymes, inhibits proliferation, and induces apoptosis in U-373MG glioma cells.
2004, Pubmed
Acevedo-Duncan,
Aloe-emodin modulates PKC isozymes, inhibits proliferation, and induces apoptosis in U-373MG glioma cells.
2004,
Pubmed
Albrecht,
Glutamine in the central nervous system: function and dysfunction.
2007,
Pubmed
Armano,
Localization and functional relevance of system a neutral amino acid transporters in cultured hippocampal neurons.
2002,
Pubmed
Bacci,
Block of glutamate-glutamine cycle between astrocytes and neurons inhibits epileptiform activity in hippocampus.
2002,
Pubmed
Battaglioli,
Stimulation of synaptosomal gamma-aminobutyric acid synthesis by glutamate and glutamine.
1990,
Pubmed
Beckman,
Multiple G protein-coupled receptors initiate protein kinase C redistribution of GABA transporters in hippocampal neurons.
1999,
Pubmed
Boulland,
Highly differential expression of SN1, a bidirectional glutamine transporter, in astroglia and endothelium in the developing rat brain.
2003,
Pubmed
Boulland,
Cell-specific expression of the glutamine transporter SN1 suggests differences in dependence on the glutamine cycle.
2002,
Pubmed
Boulland,
Expression of the vesicular glutamate transporters during development indicates the widespread corelease of multiple neurotransmitters.
2004,
Pubmed
Bröer,
Astroglial glutamine transport by system N is upregulated by glutamate.
2004,
Pubmed
,
Xenbase
Chaudhry,
Glutamate transporters in glial plasma membranes: highly differentiated localizations revealed by quantitative ultrastructural immunocytochemistry.
1995,
Pubmed
Chaudhry,
Coupled and uncoupled proton movement by amino acid transport system N.
2001,
Pubmed
,
Xenbase
Chaudhry,
The glutamine commute: take the N line and transfer to the A.
2002,
Pubmed
Chaudhry,
Pharmacology of neurotransmitter transport into secretory vesicles.
2008,
Pubmed
Chaudhry,
Molecular analysis of system N suggests novel physiological roles in nitrogen metabolism and synaptic transmission.
1999,
Pubmed
Chaudhry,
Glutamine uptake by neurons: interaction of protons with system a transporters.
2002,
Pubmed
Collarini,
Mechanisms of transport of amino acids across membranes.
1987,
Pubmed
Croquet,
Five isoenzymes of protein kinase C are expressed in normal and STZ-diabetic rat hepatocytes: effect of phorbol 12-myristate 13-acetate.
1996,
Pubmed
Danbolt,
Glutamate uptake.
2001,
Pubmed
Daniels,
Regulated trafficking of the human dopamine transporter. Clathrin-mediated internalization and lysosomal degradation in response to phorbol esters.
1999,
Pubmed
Dawson,
Parallel changes in amino acid transport and protein kinase C localization in LLC-PK1 cells treated with TPA or diradylglycerols.
1987,
Pubmed
Efendiev,
Contrary to rat-type, human-type Na,K-ATPase is phosphorylated at the same amino acid by hormones that produce opposite effects on enzyme activity.
2006,
Pubmed
Fricke,
Glutamine uptake by System A transporters maintains neurotransmitter GABA synthesis and inhibitory synaptic transmission.
2007,
Pubmed
Furness,
A quantitative assessment of glutamate uptake into hippocampal synaptic terminals and astrocytes: new insights into a neuronal role for excitatory amino acid transporter 2 (EAAT2).
2008,
Pubmed
Gammelsaeter,
Complementary expression of SN1 and SAT2 in the islets of Langerhans suggests concerted action of glutamine transport in the regulation of insulin secretion.
2009,
Pubmed
Gao,
Structure and mechanism of an amino acid antiporter.
2009,
Pubmed
Gebhardt,
Hormonal regulation of amino acid transport system N in primary cultures of rat hepatocytes.
1987,
Pubmed
González,
Evidence that protein kinase Calpha interacts with and regulates the glial glutamate transporter GLT-1.
2005,
Pubmed
Gu,
Differential regulation of amino acid transporter SNAT3 by insulin in hepatocytes.
2005,
Pubmed
Guillet,
Differential regulation by protein kinases of activity and cell surface expression of glutamate transporters in neuron-enriched cultures.
2005,
Pubmed
Hatanaka,
Amino acid transporter ATA2 is stored at the trans-Golgi network and released by insulin stimulus in adipocytes.
2006,
Pubmed
Haug,
Phosphorylation of the inositol 1,4,5-trisphosphate receptor by cyclic nucleotide-dependent kinases in vitro and in rat cerebellar slices in situ.
1999,
Pubmed
Huang,
Immunocytochemical localization of protein kinase C isozymes in rat brain.
1988,
Pubmed
Hundal,
Characteristics of L-glutamine transport in perfused rat skeletal muscle.
1987,
Pubmed
Jayanthi,
Evidence for biphasic effects of protein kinase C on serotonin transporter function, endocytosis, and phosphorylation.
2005,
Pubmed
Jenstad,
System A transporter SAT2 mediates replenishment of dendritic glutamate pools controlling retrograde signaling by glutamate.
2009,
Pubmed
Kalandadze,
Protein kinase C activation decreases cell surface expression of the GLT-1 subtype of glutamate transporter. Requirement of a carboxyl-terminal domain and partial dependence on serine 486.
2002,
Pubmed
Karl,
Insulin-like growth factor-1 stimulates amino acid uptake by the cultured human placental trophoblast.
1995,
Pubmed
Liang,
Dynamic regulation of synaptic GABA release by the glutamate-glutamine cycle in hippocampal area CA1.
2006,
Pubmed
Ling,
Involvement of transporter recruitment as well as gene expression in the substrate-induced adaptive regulation of amino acid transport system A.
2001,
Pubmed
Liu,
Platelet-derived growth factor stimulates LAT1 gene expression in vascular smooth muscle: role in cell growth.
2004,
Pubmed
Lohmann,
Stimulation of rat hepatic amino acid transport by burn injury.
1998,
Pubmed
McCarthy,
Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue.
1980,
Pubmed
Melikian,
Neurotransmitter transporter trafficking: endocytosis, recycling, and regulation.
2004,
Pubmed
Melikian,
Membrane trafficking regulates the activity of the human dopamine transporter.
1999,
Pubmed
Newpher,
Glutamate receptor dynamics in dendritic microdomains.
2008,
Pubmed
Onan,
Type I diabetes affects skeletal muscle glutamine uptake in a fiber-specific manner.
2005,
Pubmed
O'Shea,
Effects of lipopolysaccharide on glial phenotype and activity of glutamate transporters: Evidence for delayed up-regulation and redistribution of GLT-1.
2006,
Pubmed
Palacín,
Molecular biology of mammalian plasma membrane amino acid transporters.
1998,
Pubmed
Palii,
Transcriptional control of the human sodium-coupled neutral amino acid transporter system A gene by amino acid availability is mediated by an intronic element.
2004,
Pubmed
Pastor-Anglada,
Mechanisms implicated in the response of system a to hypertonic stress and amino acid deprivation still can be different.
2005,
Pubmed
Peyrollier,
L-leucine availability regulates phosphatidylinositol 3-kinase, p70 S6 kinase and glycogen synthase kinase-3 activity in L6 muscle cells: evidence for the involvement of the mammalian target of rapamycin (mTOR) pathway in the L-leucine-induced up-regulation of system A amino acid transport.
2000,
Pubmed
Pfaff,
Immunolocalization of protein kinase C isoenzymes alpha, beta1 and betaII in rat kidney.
1999,
Pubmed
Rae,
Inhibition of glutamine transport depletes glutamate and GABA neurotransmitter pools: further evidence for metabolic compartmentation.
2003,
Pubmed
Ramamoorthy,
Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants.
1999,
Pubmed
Robinson,
Regulated trafficking of neurotransmitter transporters: common notes but different melodies.
2002,
Pubmed
Rodriguez,
Phosphorylation of glutathione-S-transferase by protein kinase C-alpha implications for affinity-tag purification.
2005,
Pubmed
Rothman,
In vivo NMR studies of the glutamate neurotransmitter flux and neuroenergetics: implications for brain function.
2003,
Pubmed
Sato,
The recombinant GABA transporter GAT1 is downregulated upon activation of protein kinase C.
1995,
Pubmed
Scannevin,
Postsynaptic organization and regulation of excitatory synapses.
2000,
Pubmed
Shaffer,
Structure and mechanism of a Na+-independent amino acid transporter.
2009,
Pubmed
Shotwell,
The regulation of neutral amino acid transport in mammalian cells.
1983,
Pubmed
Sneddon,
Amelioration of denervation-induced atrophy by clenbuterol is associated with increased PKC-alpha activity.
2000,
Pubmed
Solbu,
SAT1, A Glutamine Transporter, is Preferentially Expressed in GABAergic Neurons.
2010,
Pubmed
Solbu,
Induction and targeting of the glutamine transporter SN1 to the basolateral membranes of cortical kidney tubule cells during chronic metabolic acidosis suggest a role in pH regulation.
2005,
Pubmed
Sorkin,
Signal transduction and endocytosis: close encounters of many kinds.
2002,
Pubmed
Sundberg,
The evolutionary history and tissue mapping of amino acid transporters belonging to solute carrier families SLC32, SLC36, and SLC38.
2008,
Pubmed
Susarla,
Internalization and degradation of the glutamate transporter GLT-1 in response to phorbol ester.
2008,
Pubmed
Tani,
Glutamine is required for persistent epileptiform activity in the disinhibited neocortical brain slice.
2010,
Pubmed
Tian,
Protein kinase C in beta-cells: expression of multiple isoforms and involvement in cholinergic stimulation of insulin secretion.
1996,
Pubmed
Vanoni,
Increased internalisation and degradation of GLT-1 glial glutamate transporter in a cell model for familial amyotrophic lateral sclerosis (ALS).
2004,
Pubmed
Wang,
Syntaxin 1A inhibits GABA flux, efflux, and exchange mediated by the rat brain GABA transporter GAT1.
2003,
Pubmed
,
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