scholarly journals Aquaporin-4–binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2

2008 ◽  
Vol 205 (11) ◽  
pp. 2473-2481 ◽  
Author(s):  
Shannon R. Hinson ◽  
Shanu F. Roemer ◽  
Claudia F. Lucchinetti ◽  
James P. Fryer ◽  
Thomas J. Kryzer ◽  
...  
Keyword(s):  
Neuromyelitis Optica ◽  
Excitatory Amino Acid ◽  
Membrane Integrity ◽  
Glutamate Transport ◽  
Aquaporin 4 ◽  
Macromolecular Complex ◽  
Excitatory Amino Acid Transporter ◽  
Demyelinating Disorders ◽  
Cns Lesions ◽  
Active Complement

Neuromyelitis optica (NMO)-immunoglobulin G (IgG) is a clinically validated serum biomarker that distinguishes relapsing central nervous system (CNS) inflammatory demyelinating disorders related to NMO from multiple sclerosis. This autoantibody targets astrocytic aquaporin-4 (AQP4) water channels. Clinical, radiological, and immunopathological data suggest that NMO-IgG might be pathogenic. Characteristic CNS lesions exhibit selective depletion of AQP4, with and without associated myelin loss; focal vasculocentric deposits of IgG, IgM, and complement; prominent edema; and inflammation. The effect of NMO-IgG on astrocytes has not been studied. In this study, we demonstrate that exposure to NMO patient serum and active complement compromises the membrane integrity of CNS-derived astrocytes. Without complement, astrocytic membranes remain intact, but AQP4 is endocytosed with concomitant loss of Na+-dependent glutamate transport and loss of the excitatory amino acid transporter 2 (EAAT2) . Our data suggest that EAAT2 and AQP4 exist in astrocytic membranes as a macromolecular complex. Transport-competent EAAT2 protein is up-regulated in differentiating astrocyte progenitors and in nonneural cells expressing AQP4 transgenically. Marked reduction of EAAT2 in AQP4-deficient regions of NMO patient spinal cord lesions supports our immunocytochemical and immunoprecipitation data. Thus, binding of NMO-IgG to astrocytic AQP4 initiates several potentially neuropathogenic mechanisms: complement activation, AQP4 and EAAT2 down-regulation, and disruption of glutamate homeostasis.

EAAT1 is involved in transport ofl-glutamate during differentiation of the Caco-2 cell line

2000 ◽  
Vol 279 (2) ◽  
pp. G366-G373 ◽  
Author(s):  
Agnès Mordrelle ◽  
Eric Jullian ◽  
Cyrille Costa ◽  
Estelle Cormet-Boyaka ◽  
Robert Benamouzig ◽  
...  
Keyword(s):  
Amino Acid ◽  
Cell Line ◽  
Excitatory Amino Acid ◽  
Kinetic Studies ◽  
Glutamate Transport ◽  
Hill Coefficient ◽  
Amino Acid Transporters ◽  
Intestinal Epithelial ◽  
Transport Capacity ◽  
Excitatory Amino Acid Transporter

Little is known concerning the expression of amino acid transporters during intestinal epithelial cell differentiation. The transport mechanism ofl-glutamate and its regulation during the differentiation process were investigated using the human intestinal Caco-2 cell line. Kinetic studies demonstrated the presence of a single, high-affinity,d-aspartate-sensitive l-glutamate transport system in both confluent and fully differentiated Caco-2 cells. This transport was clearly Na+ dependent, with a Hill coefficient of 2.9 ± 0.3, suggesting a 3 Na+-to-1 glutamate stoichiometry and corresponding to the well-characterized XA,G − system. The excitatory amino acid transporter (EAAT)1 transcript was consistently expressed in the Caco-2 cell line, whereas the epithelial and neuronal EAAT3 transporter was barely detected. In contrast with systems B0 and y+, which have previously been reported to be downregulated when Caco-2 cells stop proliferating, l-glutamate transport capacity was found to increase steadily between day 8 and day 17. This increase was correlated with the level of EAAT1 mRNA, which might reflect an increase in EAAT1 gene transcription and/or stabilization of the EAAT1 transcript.

Introduction: Glutamate transport, metabolism, and physiological responses

1999 ◽  
Vol 277 (4) ◽  
pp. F477-F480 ◽  
Author(s):  
M. A. Hediger ◽  
T. C. Welbourne
Keyword(s):  
Amino Acid ◽  
San Francisco ◽  
Excitatory Amino Acid ◽  
Glutamate Transport ◽  
Glutamine Metabolism ◽  
Epithelial Cell Line ◽  
Amino Acid Transporters ◽  
Excitatory Amino Acid Transporter ◽  
Renal Epithelial Cell

The material covered in this set of articles was originally presented at Experimental Biology ’98, in San Francisco, CA, on April 20, 1998. Here, the participants recount important elements of current research on the role of glutamate transporter activity in cellular signaling, metabolism, and organ function. W. A. Fairman and S. G. Amara discuss the five subtypes of human excitatory amino acid transporters, with emphasis on the EAAT4 subtype. M. A. Hediger discusses the expression and action of EAAC1 subtype of the human excitatory amino acid transporter. I. Nissim provides an overview of the significant role of pH in regulating Gln/Glu metabolism in the kidney, liver, and brain. J. D. McGivan and B. Nicholson describe some characteristics of glutamate transport regulation with regard to a specific experimental model of the bovine renal epithelial cell line NBL-1. Finally, T. C. Welbourne and J. C. Matthews introduce the “functional unit” concept of glutamate transport and how this relates to both glutamine metabolism and paracellular permeability.

Water and urea permeation pathways of the human excitatory amino acid transporter EAAT1

2011 ◽  
Vol 439 (2) ◽  
pp. 333-340 ◽  
Author(s):  
Robert J. Vandenberg ◽  
Cheryl A. Handford ◽  
Ewan M. Campbell ◽  
Renae M. Ryan ◽  
Andrea J. Yool
Keyword(s):  
Amino Acid ◽  
Water Transport ◽  
Transport Process ◽  
Excitatory Amino Acid ◽  
Anion Channel ◽  
Glutamate Transporters ◽  
Amino Acid Transporter ◽  
Glutamate Transport ◽  
Excitatory Amino Acid Transporter ◽  
Permeation Properties

Glutamate transport is coupled to the co-transport of 3 Na+ and 1 H+ followed by the counter-transport of 1 K+. In addition, glutamate and Na+ binding to glutamate transporters generates an uncoupled anion conductance. The human glial glutamate transporter EAAT1 (excitatory amino acid transporter 1) also allows significant passive and active water transport, which suggests that water permeation through glutamate transporters may play an important role in glial cell homoeostasis. Urea also permeates EAAT1 and has been used to characterize the permeation properties of the transporter. We have previously identified a series of mutations that differentially affect either the glutamate transport process or the substrate-activated channel function of EAAT1. The water and urea permeation properties of wild-type EAAT1 and two mutant transporters were measured to identify which permeation pathway facilitates the movement of these molecules. We demonstrate that there is a significant rate of L-glutamate-stimulated passive and active water transport. Both the passive and active L-glutamate-stimulated water transport is most closely associated with the glutamate transport process. In contrast, L-glutamate-stimulated [14C]urea permeation is associated with the anion channel of the transporter. However, there is also likely to be a transporter-specific, but glutamate independent, flux of water via the anion channel.

Glutamate metabolism in HIV-infected macrophages: implications for the CNS

2006 ◽  
Vol 291 (4) ◽  
pp. C618-C626 ◽  
Author(s):  
Fabrice Porcheray ◽  
Cathie Léone ◽  
Boubekeur Samah ◽  
Anne-Cécile Rimaniol ◽  
Nathalie Dereuddre-Bosquet ◽  
...  
Keyword(s):  
Gene Expression ◽  
Glutamine Synthetase ◽  
Hiv Infection ◽  
Excitatory Amino Acid ◽  
Glutamate Uptake ◽  
Glutamate Transport ◽  
Activated Macrophages ◽  
Glutamate Metabolism ◽  
Excitatory Amino Acid Transporter ◽  
Hiv Encephalitis

Central nervous system disorders are still a common complication of human immunodeficiency virus (HIV) infection and can lead to dementia and death. They are mostly the consequences of an inflammatory macrophagic activation and relate to glutamate-mediated excitotoxicity. However, recent studies also suggest neuroprotective aspects of macrophage activation through the expression of glutamate transporters and glutamine synthetase. We thus aimed to study whether HIV infection or activation of macrophages could modulate glutamate metabolism in these cells. We assessed the effect of HIV infection on glutamate transporter expression as well as on glutamate uptake by macrophages and showed that glutamate transport was partially decreased in the course of virus replication, whereas excitatory amino acid transporter-2 (EAAT-2) gene expression was dramatically increased. The consequences of HIV infection on glutamine synthetase were also measured and for the first time we show the functional expression of this key enzyme in macrophages. This expression was repressed during virus production. We then quantified EAAT-1 and EAAT-2 gene expression as well as glutamate uptake in differentially activated macrophages and show that the effects of HIV are not directly related to pro- or anti-inflammatory mediators. Finally, this study shows that glutamate transport by macrophages is less affected than what has been described in astrocytes. Macrophages may thus play a role in neuroprotection against glutamate in the infected brain, through their expression of both EAATs and glutamine synthetase. Because glutamate metabolism by activated macrophages is sensitive to both HIV infection and inflammation, it may thus be of potential interest as a therapeutic target in HIV encephalitis.

Elevated ammonium levels: differential acute effects on three glutamate transporter isoforms

2012 ◽  
Vol 302 (6) ◽  
pp. C880-C891 ◽  
Author(s):  
Rikke Søgaard ◽  
Ivana Novak ◽  
Nanna MacAulay
Keyword(s):  
Excitatory Amino Acid ◽  
Glutamate Uptake ◽  
Brain Slices ◽  
Glutamate Transporter ◽  
Surface Expression ◽  
Glutamate Transport ◽  
Excitatory Amino Acid Transporter ◽  
Ph Buffering ◽  
Specific Effects ◽  
Intracellular Alkalinization

Increased ammonium (NH4+/NH3) in the brain is a significant factor in the pathophysiology of hepatic encephalopathy, which involves altered glutamatergic neurotransmission. In glial cell cultures and brain slices, glutamate uptake either decreases or increases following acute ammonium exposure but the factors responsible for the opposing effects are unknown. Excitatory amino acid transporter isoforms EAAT1, EAAT2, and EAAT3 were expressed in Xenopus oocytes to study effects of ammonium exposure on their individual function. Ammonium increased EAAT1- and EAAT3-mediated [3H]glutamate uptake and glutamate transport currents but had no effect on EAAT2. The maximal EAAT3-mediated glutamate transport current was increased but the apparent affinities for glutamate and Na+ were unaltered. Ammonium did not affect EAAT3-mediated transient currents, indicating that EAAT3 surface expression was not enhanced. The ammonium-induced stimulation of EAAT3 increased with increasing extracellular pH, suggesting that the gaseous form NH3 mediates the effect. An ammonium-induced intracellular alkalinization was excluded as the cause of the enhanced EAAT3 activity because 1) ammonium acidified the oocyte cytoplasm, 2) intracellular pH buffering with MOPS did not reduce the stimulation, and 3) ammonium enhanced pH-independent cysteine transport. Our data suggest that the ammonium-elicited uptake stimulation is not caused by intracellular alkalinization or changes in the concentrations of cotransported ions but may be due to a direct effect on EAAT1/EAAT3. We predict that EAAT isoform-specific effects of ammonium combined with cell-specific differences in EAAT isoform expression may explain the conflicting reports on ammonium-induced changes in glial glutamate uptake.

NEUROMYELITIS OPTICA (AQUAPORIN-4 ANTIBODY-POSITIVE) WITH OVERLAPPING ANTI NMDAR ENCEPHALITIS

2021 ◽  
pp. 45-47
Author(s):  
Kirtan Nandlalbhai Patolia ◽  
Dixit Prakashbhai Dhorajiya ◽  
Nirav Ashokbhai Chavda ◽  
Jitendra. H. Parikh
Keyword(s):  
Neuromyelitis Optica ◽  
Psychiatric Symptoms ◽  
Autoimmune Encephalitis ◽  
Aquaporin 4 ◽  
Abnormal Behavior ◽  
Atypical Symptoms ◽  
Nmdar Encephalitis ◽  
Mog Antibodies ◽  
Demyelinating Disorders ◽  
Aquaporin 4 Antibody

Neuromyelitis Optica (NMO) is an inammatory CNS syndrome distinct from multiple sclerosis (MS) that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG) or rarely with Anti -MOG antibodies (Myelin Oligodendrocyte Glycoprotein-IgG). Anti-NMDAR encephalitis classically presents with Neuro-psychiatric symptoms, including memory decits, seizures, frequent dyskinesia, autonomic dysfunction, reduced consciousness, and hypoventilation. Although rare, the coexistence of autoimmune encephalitis with demyelinating disorders should be considered in presence of atypical symptoms. We present a case of a patient with overlapping clinical features of NMOSD and Anti-NMDAR encephalitis presenting with difculty in voiding urine, constipation, abnormal behavior, and cognitive impairment as the chief ndings on presentation.

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