Glutamate transporter EAAT2: regulation, function, and potential as a therapeutic target for neurological and psychiatric disease

Takahashi, Kou; Foster, Joshua B.; Lin, Chien‐liang Glenn

doi:10.1007/s00018-015-1937-8

Cited by 153 publications

(122 citation statements)

References 282 publications

(178 reference statements)

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“…The entire process is regulated by protein-protein interactions and phosphorylation, and is highly responsive to immune influences. Immune mediators (such as TNF) regulate membrane trafficking and recycling of EAATs either alone or in association with several neurohumoral influences, including growth factors and neuropeptides (Gras et al, 2012;Takahashi et al, 2015). As mentioned previously, EAATs are expressed on astrocytes and oligodendrocyte cells both in resting and during activation states, whereas microglia express these transporters only when activated by immune factors such as LPS (Persson et al, 2005).…”

Section: Eaatsmentioning

confidence: 95%

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Haroon

Miller

Sanacora

2016

Neuropsychopharmacol

412

299

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Increasing data indicate that inflammation and alterations in glutamate neurotransmission are two novel pathways to pathophysiology in mood disorders. The primary goal of this review is to illustrate how these two pathways may converge at the level of the glia to contribute to neuropsychiatric disease. We propose that a combination of failed clearance and exaggerated release of glutamate by glial cells during immune activation leads to glutamate increases and promotes aberrant extrasynaptic signaling through ionotropic and metabotropic glutamate receptors, ultimately resulting in synaptic dysfunction and loss. Furthermore, glutamate diffusion outside the synapse can lead to the loss of synaptic fidelity and specificity of neurotransmission, contributing to circuit dysfunction and behavioral pathology. This review examines the fundamental role of glia in the regulation of glutamate, followed by a description of the impact of inflammation on glial glutamate regulation at the cellular, molecular, and metabolic level. In addition, the role of these effects of inflammation on glia and glutamate in mood disorders will be discussed along with their translational implications.

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Section: Eaatsmentioning

confidence: 95%

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Haroon

Miller

Sanacora

2016

Neuropsychopharmacol

412

299

View full text Add to dashboard Cite

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“…The expression or activity of EAAT2 is regulated both transcriptionally and post‐transcriptionally (Grewer, Gameiro, & Rauen, 2014; Takahashi, Foster, & Lin, 2015a). Therefore, theoretically, upregulation of EAAT2 could be achieved at transcriptional or translational level.…”

Section: Potential Therapeutic Targets In Astrocytesmentioning

confidence: 99%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

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Astrocytes are key homeostatic cells of the central nervous system. They cooperate with neurons at several levels, including ion and water homeostasis, chemical signal transmission, blood flow regulation, immune and oxidative stress defense, supply of metabolites and neurogenesis. Astroglia is also important for viability and maturation of stem‐cell derived neurons. Neurons critically depend on intrinsic protective and supportive properties of astrocytes. Conversely, all forms of pathogenic stimuli which disturb astrocytic functions compromise neuronal functionality and viability. Support of neuroprotective functions of astrocytes is thus an important strategy for enhancing neuronal survival and improving outcomes in disease states. In this review, we first briefly examine how astrocytic dysfunction contributes to major neurological disorders, which are traditionally associated with malfunctioning of processes residing in neurons. Possible molecular entities within astrocytes that could underpin the cause, initiation and/or progression of various disorders are outlined. In the second section, we explore opportunities enhancing neuroprotective function of astroglia. We consider targeting astrocyte‐specific molecular pathways which are involved in neuroprotection or could be expected to have a therapeutic value. Examples of those are oxidative stress defense mechanisms, glutamate uptake, purinergic signaling, water and ion homeostasis, connexin gap junctions, neurotrophic factors and the Nrf2‐ARE pathway. We propose that enhancing the neuroprotective capacity of astrocytes is a viable strategy for improving brain resilience and developing new therapeutic approaches.

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“…The major role of these transporters is to keep glutamate concentrations in the synaptic cleft below excitotoxic levels (4), and their dysfunction in the central nervous system is associated with many neurological diseases, such as epilepsy, Alzheimer's disease, and amyotrophic lateral sclerosis (5). The crystal structures of Glt Ph (6,7) provided a breakthrough in the understanding of the ion-coupled transport mechanism.…”

mentioning

confidence: 99%

Direct visualization of glutamate transporter elevator mechanism by high-speed AFM

Ruan

Miyagi

Wang

et al. 2017

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

111

107

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Glutamate transporters are essential for recovery of the neurotransmitter glutamate from the synaptic cleft. Crystal structures in the outward-and inward-facing conformations of a glutamate transporter homolog from archaebacterium Pyrococcus horikoshii, sodium/aspartate symporter Glt Ph , suggested the molecular basis of the transporter cycle. However, dynamic studies of the transport mechanism have been sparse and indirect. Here we present highspeed atomic force microscopy (HS-AFM) observations of membranereconstituted Glt Ph at work. HS-AFM movies provide unprecedented real-space and real-time visualization of the transport dynamics. Our results show transport mediated by large amplitude 1.85-nm "elevator" movements of the transport domains consistent with previous crystallographic and spectroscopic studies. Elevator dynamics occur in the absence and presence of sodium ions and aspartate, but stall in sodium alone, providing a direct visualization of the ion and substrate symport mechanism. We show unambiguously that individual protomers within the trimeric transporter function fully independently.Glt Ph | HS-AFM | transporter | elevator mechanism | dynamics

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Glutamate transporter EAAT2: regulation, function, and potential as a therapeutic target for neurological and psychiatric disease

Cited by 153 publications

References 282 publications

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Direct visualization of glutamate transporter elevator mechanism by high-speed AFM

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