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Last update 23 Jan 2025

EAAT1

Last update 23 Jan 2025

Basic Info

Synonyms

EA6, EAAT1, Excitatory amino acid transporter 1

+ [8]

Introduction

Sodium-dependent, high-affinity amino acid transporter that mediates the uptake of L-glutamate and also L-aspartate and D-aspartate (PubMed:7521911, PubMed:8123008, PubMed:20477940, PubMed:26690923, PubMed:28032905, PubMed:28424515). Functions as a symporter that transports one amino acid molecule together with two or three Na(+) ions and one proton, in parallel with the counter-transport of one K(+) ion (PubMed:20477940). Mediates Cl(-) flux that is not coupled to amino acid transport; this avoids the accumulation of negative charges due to aspartate and Na(+) symport (PubMed:20477940). Plays a redundant role in the rapid removal of released glutamate from the synaptic cleft, which is essential for terminating the postsynaptic action of glutamate (By similarity).

Drugs associated with EAAT1

UCPH-101

Target

EAAT1

Mechanism

EAAT1 blockers

Active Org.

University of Copenhagen

Originator Org.

University of Copenhagen

Active Indication-

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Analogue 1o(University of Copenhagen)

Target

EAAT1

Mechanism

EAAT1 blockers

Active Org.

University of Copenhagen

Originator Org.

University of Copenhagen

Active Indication-

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

GDNF

Target

EAAT1

Mechanism

EAAT1 agonists

Active Org.

Fudan University

Originator Org.-

Active Indication

Diabetic Retinopathy

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with EAAT1

100 Translational Medicine associated with EAAT1

0 Patents (Medical) associated with EAAT1

1,597

Literatures (Medical) associated with EAAT1

01 Nov 2025·Neural Regeneration Research

The sexually dimorphic expression of glutamate transporters and their implication in pain after spinal cord injury

Article

Author: Rivera, Samuel E. Ocasio ; Salgado, Iris K. ; Torrado-Tapias, Aranza I. ; Miranda, Jorge D. ; Rivera, Luis H. Pagan ; Colón-Mercado, Jennifer M. ; Bracho-Rincon, Dina P. ; Santiago, José M.

JOURNAL/nrgr/04.03/01300535-202511000-00033/figure1/v/2024-12-20T164640Z/r/image-tiff In addition to the loss of motor function, ~60% of patients develop pain after spinal cord injury. The cellular-molecular mechanisms are not well understood, but the data suggests that plasticity within the rostral, epicenter, and caudal penumbra of the injury site initiates a cellular-molecular interplay that acts as a rewiring mechanism leading to central neuropathic pain. Sprouting can lead to the formation of new connections triggering abnormal sensory transmission. The excitatory glutamate transporters are responsible for the reuptake of extracellular glutamate which makes them a critical target to prevent neuronal hyperexcitability and excitotoxicity. Our previous studies showed a sexually dimorphic therapeutic window for spinal cord injury after treatment with the selective estrogen receptor modulator tamoxifen. In this study, we investigated the anti-allodynic effects of tamoxifen in male and female rats with spinal cord injury. We hypothesized that tamoxifen exerts anti-allodynic effects by increasing the expression of glutamate transporters, leading to reduced hyperexcitability of the secondary neuron or by decreasing aberrant sprouting. Male and female rats received a moderate contusion to the thoracic spinal cord followed by subcutaneous slow-release treatment of tamoxifen or matrix pellets as a control (placebo). We used von Frey monofilaments and the “up-down method” to evaluate mechanical allodynia. Tamoxifen treatment decreased allodynia only in female rats with spinal cord injury revealing a sex-dependent effect. The expression profile of glutamatergic transporters (excitatory amino acid transporter 1/glutamate aspartate transporter and excitatory amino acid transporter 2/glutamate transporter-1) revealed a sexual dimorphism in the rostral, epicenter, and caudal areas of the spinal cord with a pattern of expression primarily on astrocytes. Female rodents showed a significantly higher level of excitatory amino acid transporter-1 expression while male rodents showed increased excitatory amino acid transporter-2 expression compared with female rodents. Analyses of peptidergic (calcitonin gene-related peptide-α) and non-peptidergic (isolectin B4) fibers outgrowth in the dorsal horn after spinal cord injury showed an increased calcitonin gene-related peptide-α/ isolectin B4 ratio in comparison with sham, suggesting increased receptive fields in the dorsal horn. Although the behavioral assay shows decreased allodynia in tamoxifen-treated female rats, this was not associated with overexpression of glutamate transporters or alterations in the dorsal horn laminae fibers at 28 days post-injury. Our findings provide new evidence of the sexually dimorphic expression of glutamate transporters in the spinal cord. The dimorphic expression revealed in this study provides a therapeutic opportunity for treating chronic pain, an area with a critical need for treatment.

01 Mar 2025·Experimental Neurology

Microglial cell proliferation is regulated, in part, by reactive astrocyte ETBR signaling after ischemic stroke

Article

Author: Reed, Leah F ; Del Rio-Guerra, Roxana ; Poynter, Matthew E ; McInnis, John J ; Spees, Jeffrey L ; LeComte, Matthew D ; Torsney, Emily E

Reciprocal communication between reactive astrocytes and microglial cells provides local, coordinated control over critical processes such as neuroinflammation, neuroprotection, and scar formation after CNS injury, but is poorly understood. The vasoactive peptide hormone endothelin (ET) is released and/or secreted by endothelial cells, microglial cells and astrocytes early after ischemic stroke and other forms of brain injury. To better understand glial cell communication after stroke, we sought to identify paracrine effectors produced and secreted downstream of astroglial endothelin receptor B (ETB_R) signaling. Using a genetic loss-of-function screen, we identified angiopoietin-2 (Ang-2) as a factor produced by reactive astrocytes in response to ET. In experiments with primary adult astrocytes stimulated by IRL1620, a specific ETB_R agonist, we found that ERK1/2 and NFkB mediated the effects of ET on Ang-2 production. To determine astroglial Ang-2 levels in vivo, reactive astrocytes expressing the high affinity glutamate transporter (GLAST, EAAT1) were isolated by magnetic-activated cell sorting 3 days after stroke. Astrocytes obtained from the ipsilateral hemisphere expressed significantly more Ang-2 compared with astrocytes isolated from the contralateral hemisphere, or from cortices of sham-operated (control) mice. Notably, analysis of microglia sorted from CX3CR1-eGFP mice demonstrated increased cell surface expression of Tie-2, the Ang-2 receptor, on cells obtained from ipsilateral versus contralateral tissue. Addition of recombinant Ang-2 to astrocyte-conditioned medium significantly increased the number of SIM-A9 murine microglial cells cultured under hypoxic conditions (1 % oxygen for 48 h). In transgenic GFAP-CreER™-EDNRB-^fl/fl mice with stroke, conditional knockout of astroglial ETB_R significantly decreased the number of proliferating cells in the peri-infarct area with a microglial phenotype (Ki67⁺/CD11b⁺). Our results indicate that Ang-2, and possibly other paracrine effectors functioning downstream of astroglial ETB_R signaling, are important mediators of microglial cell dynamics after stroke.

01 Feb 2025·Neuroscience

Upregulated excitatory amino acid transporter 1 (EAAT1) expression in the human medial temporal lobe in Alzheimer’s disease

Article

Author: Palpagama, Thulani H ; Waldvogel, Henry J ; Faull, Richard L M ; Wood, Oliver W G ; Kwakowsky, Andrea ; Turner, Clinton ; Yeung, Jason H Y

Alzheimer's disease (AD) is a growing health problem worldwide, particularly in the developed world due to an ageing population. Glutamate excitotoxicity plays a major role in the pathophysiology of AD, and glutamate re-uptake is controlled by excitatory amino acid transporters (EAATs). The EAAT2 isoform is the predominant transporter involved in glutamate reuptake, therefore EAAT1 has not been the focus of AD research. We investigated the layer-specific expression of EAAT1 in human medial temporal lobe regions such as the hippocampus, subiculum, entorhinal cortex and superior temporal gyrus, using fluorescent immunohistochemistry and laser scanning confocal microscopy in human post-mortem tissue. We observed low EAAT1 immunoreactivity in control cases, but upregulated labeling in AD across several brain regions of the medial temporal lobe. Significantly higher integrated density in AD cases was observed in the str. oriens and str. radiatum of the CA2 region, the str. pyramidale of CA3, and the str. moleculare and str. granulosum of the DG. Labeling of EAAT1 appeared astrocytic in nature, showing close association with astrocytic processes in AD cases. We also report that a higher EAAT1 density was positively correlated with the age of AD cases, but this relationship was not observed in control cases. Overall, our results indicate an upregulation of EAAT1 across several hippocampal subregions and layers in AD cases, indicating a potential physiological role for this transporter that needs further investigation.

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EAAT1

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