Fast Removal of Synaptic Glutamate by Postsynaptic Transporters

Auger, Céline; Attwell, David

doi:10.1016/s0896-6273(00)00132-x

Cited by 158 publications

(143 citation statements)

References 51 publications

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“…Several groups have proposed a model in which a proton binds along with substrate from the outside before and during activation of the anion conductance, and is subsequently cotransported with the substrate (7,34,35). In an alternative model, a proton is transported into the cell during the countertransport of a potassium ion (18). Here we show that, in the absence of a complete transport cycle, protons increase the apparent affinity of L-glutamate to activate the anion conductance.…”

Section: Discussionmentioning

confidence: 64%

“…In the case of the EAATs, several biophysical studies have shown that the anion current is thermodynamically uncoupled from transport, although these two activities appear to be tightly associated within the transport cycle (14)(15)(16)(17)(18). Little is known, however, about the structural relationship between substrate transport and the ion channel activity.…”

Section: Discussionmentioning

confidence: 99%

“…Although it is possible that protons bind to an allosteric site, which alters V449C kinetics only after sulfhydryl modification, the most plausible explanation for these results is that protons modulate the extracellular binding of substrate before and during activation of the anion conductance. Most kinetic models of the transport cycle describe the existence of an anion-conducting state after the substrate and cotransported ions have bound to the extracellular side of the transporter and before their translocation (14)(15)(16)(17)(18). In an alternative model the anion conducting state has been proposed to follow the translocation of substrate and cotransported ions (19).…”

Section: Discussionmentioning

confidence: 99%

“…Studies using patch clamp analyses to measure rapid transport kinetics have linked gating of the anion conductance to early steps in the transport cycle (14)(15)(16)(17)(18). Association of anion channel gating events with the translocation limb of the cycle is further supported by the observation that transporters locked in an exchange mode still mediate the anion conductance (19)(20)(21)(22)(23).…”

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confidence: 99%

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Sulfhydryl modification of V449C in the glutamate transporter EAAT1 abolishes substrate transport but not the substrate-gated anion conductance

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Shigeri

Eliasof

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Excitatory amino acid transporters (EAATs) buffer and remove synaptically released L-glutamate and maintain its concentrations below neurotoxic levels. EAATs also mediate a thermodynamically uncoupled substrate-gated anion conductance that may modulate cell excitability. Here, we demonstrate that modification of a cysteine substituted within a C-terminal domain of EAAT1 abolishes transport in both the forward and reverse directions without affecting activation of the anion conductance. EC 50s for L-glutamate and sodium are significantly lower after modification, consistent with kinetic models of the transport cycle that link anion channel gating to an early step in substrate translocation. Also, decreasing the pH from 7.5 to 6.5 decreases the EC 50 for Lglutamate to activate the anion conductance, without affecting the EC50 for the entire transport cycle. These findings demonstrate for the first time a structural separation of transport and the uncoupled anion flux. Moreover, they shed light on some controversial aspects of the EAAT transport cycle, including the kinetics of proton binding and anion conductance activation.

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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Sulfhydryl modification of V449C in the glutamate transporter EAAT1 abolishes substrate transport but not the substrate-gated anion conductance

Seal

Shigeri

Eliasof

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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“…183,184 Pharmacologic intervention in MD is associated with downregulation of the proinflammatory immune response…”

Section: Astrocytes Microglia and Type 1/type 2 Responsementioning

confidence: 99%

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

2007

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Beside the well-known deficiency in serotonergic neurotransmission as pathophysiological correlate of major depression (MD), recent evidence points to a pivotal role of increased glutamate receptor activation as well. However, cause and interaction of these neurotransmitter alterations are not understood. In this review, we present a hypothesis integrating current concepts of neurotransmission and hypothalamus-pituitary-adrenal (HPA) axis dysregulation with findings on immunological alterations and alterations in brain morphology in MD. An immune activation including increased production of proinflammatory cytokines has repeatedly been described in MD. Proinflammatory cytokines such as interleukin-2, interferon-c, or tumor necrosis factor-a activate the tryptophan-and serotonin-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Depressive states during inflammatory somatic disorders are also associated with increased proinflammatory cytokines and increased consumption of tryptophan via activation of IDO. An enhanced consumption of serotonin and its precursor tryptophan through IDO activation could well explain the reduced availability of serotonergic neurotransmission in MD. An increased activation of IDO and its subsequent enzyme kynurenine monooxygenase by proinflammatory cytokines, moreover, leads to an enhanced production of quinolinic acid, a strong agonist of the glutamatergic N-methyl-D-aspartate receptor. In inflammatory states of the central nervous system, IDO is mainly activated in microglial cells, which preferentially metabolize tryptophan to the NMDA receptor agonist quinolinic acid, whereas astrocytes -counteracting this metabolism due to the lack of an enzyme of this metabolism -have been observed to be reduced in MD. Therefore the type 1/type 2 immune response imbalance, associated with an astrocyte/microglia imbalance, leads to serotonergic deficiency and glutamatergic overproduction. Astrocytes are further strongly involved in re-uptake and metabolic conversion of glutamate. The reduced number of astrocytes could contribute to both, a diminished counterregulation of IDO activity in microglia and an altered glutamatergic neurotransmission. Further search for antidepressant agents should take into account anti-inflammatory drugs, for example, cyclooxygenase-2 inhibitors, might exert antidepressant effects by acting on serotonergic deficiency, glutamatergic hyperfunction and antagonizing neurotoxic effects of quinolinic acid. Molecular Psychiatry (2007) 12, 988-1000; doi:10.1038/sj.mp.4002006; published online 24 April 2007 Keywords: major depression; psychoneuroimmunology; IDO; glutamate; immune system; serotonin Glutamate in depressionGlutamatergic neurotransmission is involved in depression and interacts with the serotonergic and noradrenergic systems The common therapeutic mechanism of antidepressant drugs is the enhancement of serotonergic and/or noradrenergic neurotransmission. On the basis of this pharmacological profile of antidepressant drugs, neurochemical research on major depression ...

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Role of glial amino acid transporters in synaptic transmission and brain energetics

Marcaggi

Attwell

2004

Glia

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125

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This article reviews how the uptake of neurotransmitter by glial amino acid transporters limits the spatial spread of transmitter to preserve the independent operation of nearby synapses, temporally shapes postsynaptic currents, and regulates the effects of tonic transmitter release. We demonstrate the importance of amino acid uptake and recycling mechanisms for preventing the loss of energetically costly neurotransmitter from the brain, and also examine the suggestion that glutamate uptake into glia plays a key role in regulating the energy production of the brain. Finally, we assess the role of glial amino acid transporters in transmitter recycling pathways.

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Fast Removal of Synaptic Glutamate by Postsynaptic Transporters

Cited by 158 publications

References 51 publications

Sulfhydryl modification of V449C in the glutamate transporter EAAT1 abolishes substrate transport but not the substrate-gated anion conductance

Sulfhydryl modification of V449C in the glutamate transporter EAAT1 abolishes substrate transport but not the substrate-gated anion conductance

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

Role of glial amino acid transporters in synaptic transmission and brain energetics

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