Glutamate concentration in plasma, erythrocyte and muscle in relation to plasma levels of insulin-like growth factor (IGF)-I, IGF binding protein-1 and insulin in patients on haemodialysis

Filho, JC Divino; Hazel, Susan J.; Fürst, Peter; Bergström, Jonas; Hall, Kerstin

doi:10.1677/joe.0.1560519

Cited by 53 publications

(23 citation statements)

References 50 publications

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“…As IL-10 has been implicated in the inhibition of chemotactic migration of CD4 ϩ T cells (42)(43)(44), it is likely that the action of glutamate impairing IL-10 production described by others (10) occurs via another GluR type, probably iGlu3R, which participates in the regulation of adhesion and chemotactic migration (10). Thus, those iGluR expressed in resting T cells (10) stimulated by plasma glutamate (10 -50 M) (45,46) could allow the chemotactic migration of T cells in peripheral tissues. These cells could be retained in the lymph nodes for some days by the action of DC-released glutamate, the latter acting on the inducible mGlu1R expressed following productive Ag presentation.…”

Section: Discussionmentioning

confidence: 97%

Glutamate Released by Dendritic Cells as a Novel Modulator of T Cell Activation

Pacheco

Oliva

Martinez-Navío

et al. 2006

The Journal of Immunology

136

125

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Adaptive immune responses begin after productive immunosynaptic contacts formation established in secondary lymphoid organs by dendritic cells (DC) presenting the Ag to T lymphocytes. Despite its resemblance to the neurosynapse, the participation of soluble small nonpeptidic mediators in the intercellular cross-talk taking place during T cell–DC interactions remains poorly studied. In this study, we show that human DC undergoing maturation and in contact with T cells release significant amounts of glutamate, which is the main excitatory neurotransmitter in mammalians. The release of glutamate is nonvesicular and mediated by the DC-expressed Xc− cystine/glutamate antiporter. DC-derived glutamate stimulating the constitutively expressed metabotropic glutamate receptor 5 impairs T cell activation. However, after productive Ag presentation, metabotropic glutamate receptor 1 is expressed in T cells to mediate enhanced T cell proliferation and secretion of Th1 and proinflammatory cytokines. These data suggest that, during T cell–DC interaction, glutamate is a novel and highly effective regulator in the initiation of T cell-mediated immune responses.

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Section: Discussionmentioning

confidence: 97%

Glutamate Released by Dendritic Cells as a Novel Modulator of T Cell Activation

Pacheco

Oliva

Martinez-Navío

et al. 2006

The Journal of Immunology

136

125

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“…The intracellular concentration of glutamate has been determined in several studies to be between 4 and 30 mM, depending on the cell or tissue type (14,(17)(18)(19). Thus, in many cell types, the cellular concentration of glutamate is greater than or equal to the K m(Glu) for GCLC.…”

Section: Discussionmentioning

confidence: 99%

Glutamate Cysteine Ligase Catalysis

Chen

Shertzer

Schneider

et al. 2005

Journal of Biological Chemistry

213

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Glutamate cysteine ligase (GCL), which synthesizes ␥-glutamylcysteine (␥-GC), is the rate-limiting enzyme in GSH biosynthesis. ␥-GC may be produced by the catalytic subunit GCLC or by the holoenzyme (GCLholo), which comprises GCLC and the modifier subunit GCLM. The Gclm(؊/؊) knock-out mouse shows tissue levels of GSH that are between 9 and 40% of the Gclm(؉/؉) wild-type mouse. In the present study, we used recombinant GCLC and GCLM and Gclm(؊/؊) mice to examine the role of GCLM on ␥-GC synthesis by GCLholo. GCLM decreased the K m for ATP by ϳ6-fold and, similar to other species, decreased the K m for glutamate and increased the K i for feedback inhibition by GSH. Furthermore, GCLM increased by 4.4-fold the K cat for ␥-GC synthesis; this difference in catalytic efficiency of GCLholo versus GCLC allowed us to derive a mathematical relationship for ␥-GC production and to determine the relative levels of GCLholo and GCLC; in homogenates of brain, liver, and lung, the ratio of GCLC to GCLholo was 7.0, 2.0, and 3.5, respectively. In kidney, however, the relationship between GCLC and GCLholo was complicated. Kidney contains GCLholo, free GCLC, and free GCLM, and free GCLC in kidney cannot interact with GCLM. Taken together, we conclude that, in most tissues, GCLM is limiting, suggesting that an increase in GCLM alone would increase ␥-GC synthesis. On the other hand, our results from kidney suggest that ␥-GC synthesis may be controlled post-translationally.

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“…As K D values for mGlu1R and mGlu5R are in the range 10 -60 M (4), they can be activated by the glutamate present in plasma, whose concentration varies between 30 and 60 M (18,19). Chronic activation of mGlu5R by glutamate in lymphocytes may lead to receptor desensitization and/or internalization.…”

Section: Figmentioning

confidence: 99%

Group I Metabotropic Glutamate Receptors Mediate a Dual Role of Glutamate in T Cell Activation

Pacheco

Ciruela

Casadó

et al. 2004

Journal of Biological Chemistry

124

126

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Metabotropic glutamate receptors (mGluR) are present in cells of the nervous system, where they are activated by one of the main neurotransmitters, glutamate. They are also expressed in cells outside the nervous system. We identified and characterized two receptors belonging to group I mGluR, mGlu1R and mGlu5R, in human cell lines of lymphoid origin and in resting and activated lymphocytes from human peripheral blood. Both are highly expressed in the human Jurkat T cell line, whereas mGlu5R is expressed only in the human B cell line SKW6.4. In blood lymphocytes, mGlu5R is expressed constitutively, whereas mGlu1R is expressed only upon activation via the T cell receptor-CD3 complex. Group I receptors in the central nervous system are coupled to phospholipase C, whereas in blood lymphocytes, activation of mGlu5R does not trigger this signaling pathway, but instead activates adenylate cyclase. On the other hand, mGlu5R does not mediate ERK1/2 activation, whereas mGlu1R, which is coupled neither to phospholipase C nor to calcium channels and whose activation does not increase cAMP, activates the mitogen-activated protein kinase cascade. The differential expression of mGluR in resting and activated lymphocytes and the different signaling pathways that are triggered when mGlu1Rs or mGlu5Rs are activated point to a key role of glutamate in the regulation of T cell physiological function. The study of the signaling pathways (cAMP production and ERK1/2 phosphorylation) and the proliferative response obtained in the presence of glutamate analogs suggests that mGlu1R and mGlu5R have distinct functions. mGlu5R mediates the reported inhibition of cell proliferation evoked by glutamate, which is reverted by the activation of inducible mGlu1R. This is a novel non-inhibitory action mechanism for glutamate in lymphocyte activation. mGlu1R and mGlu5R thus mediate opposite glutamate effects in human lymphocytes.There is increasing evidence that the activity of T cells in the central nervous system is regulated by neurotransmitters such as dopamine, gonadotropin-releasing hormones I and II, somatostatin, substance P, calcitonin-gene-related peptide, neuropeptide Y, and glutamate (1). The latter is the main excitatory neurotransmitter in the mammalian brain involved in learning and memory, as well as in neurotoxicity, and plays a critical role in the development and progression of diverse neurological disorders. T cells can also encounter glutamate outside the brain, in "glutamate-rich" peripheral organs such as liver, kidney, lung, muscle, and blood. It is unknown whether glutamate can be released by antigen-presenting cells, thus regulating T cell activation in the immunological synapse (2).This amino acid acts at multiple receptor types, divided into two main groups: ionotropic glutamate receptors, which form ion channels and mediate fast excitatory glutamate responses, and metabotropic glutamate receptors (mGluR), 1 which are hepta-spanning membrane-receptors and belong to the superfamily of G protein-coupled receptors (3). So f...

show abstract

Glutamate concentration in plasma, erythrocyte and muscle in relation to plasma levels of insulin-like growth factor (IGF)-I, IGF binding protein-1 and insulin in patients on haemodialysis

Cited by 53 publications

References 50 publications

Glutamate Released by Dendritic Cells as a Novel Modulator of T Cell Activation

Glutamate Released by Dendritic Cells as a Novel Modulator of T Cell Activation

Glutamate Cysteine Ligase Catalysis

Group I Metabotropic Glutamate Receptors Mediate a Dual Role of Glutamate in T Cell Activation

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