The role of excitatory amino acid transporter 2 (EAAT2) in epilepsy and other neurological disorders

Alijanpour, Sahar; Miryounesi, Mohammad; Ghafouri‐Fard, Soudeh

doi:10.1007/s11011-022-01091-5

Cited by 6 publications

(3 citation statements)

References 150 publications

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“…Pharmacological administration of riluzole increases glutamate transporter expression, and in the P301L mouse model reverses glutamate related alterations and associated cognitive decline ( 141 ). Consequently, elevated levels of glutamate contribute to excitotoxicity and neuronal cell death ( 142 ). These findings collectively suggest that as the disease advances, the transporters responsible for glutamate reuptake become less effective, potentially leading to increased neuronal excitability.…”

Section: Introductionmentioning

confidence: 99%

Latest advances in mechanisms of epileptic activity in Alzheimer’s disease and dementia with Lewy Bodies

Vicente,

Addo-Osafo,

Vossel

2024

Front. Neurol.

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Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) stand as the prevailing sources of neurodegenerative dementia, impacting over 55 million individuals across the globe. Patients with AD and DLB exhibit a higher prevalence of epileptic activity compared to those with other forms of dementia. Seizures can accompany AD and DLB in early stages, and the associated epileptic activity can contribute to cognitive symptoms and exacerbate cognitive decline. Aberrant neuronal activity in AD and DLB may be caused by several mechanisms that are not yet understood. Hyperexcitability could be a biomarker for early detection of AD or DLB before the onset of dementia. In this review, we compare and contrast mechanisms of network hyperexcitability in AD and DLB. We examine the contributions of genetic risk factors, Ca2+ dysregulation, glutamate, AMPA and NMDA receptors, mTOR, pathological amyloid beta, tau and α-synuclein, altered microglial and astrocytic activity, and impaired inhibitory interneuron function. By gaining a deeper understanding of the molecular mechanisms that cause neuronal hyperexcitability, we might uncover therapeutic approaches to effectively ease symptoms and slow down the advancement of AD and DLB.

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Section: Introductionmentioning

confidence: 99%

Latest advances in mechanisms of epileptic activity in Alzheimer’s disease and dementia with Lewy Bodies

Vicente,

Addo-Osafo,

Vossel

2024

Front. Neurol.

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“…Excitatory amino acid transporters (EAATs) play a crucial role in the transport of several amino acids into the cell. Five subtypes of these EAATs exist; EAAT1–5. , All EAATs are capable of transporting glutamate, which plays a crucial role in brain functioning due to its role as a neurotransmitter. EAAT2, where SLC1A2 is the corresponding gene, is mainly expressed in astrocytes and to a lesser extent in other glial cells and neurons .…”

Section: Introductionmentioning

confidence: 99%

Still in Search for an EAAT Activator: GT949 Does Not Activate EAAT2, nor EAAT3 in Impedance and Radioligand Uptake Assays

van Veggel,

Mocking,

Sijben

et al. 2024

ACS Chem. Neurosci.

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Excitatory amino acid transporters (EAATs) are important regulators of amino acid transport and in particular glutamate. Recently, more interest has arisen in these transporters in the context of neurodegenerative diseases. This calls for ways to modulate these targets to drive glutamate transport, EAAT2 and EAAT3 in particular. Several inhibitors (competitive and noncompetitive) exist to block glutamate transport; however, activators remain scarce. Recently, GT949 was proposed as a selective activator of EAAT2, as tested in a radioligand uptake assay. In the presented research, we aimed to validate the use of GT949 to activate EAAT2-driven glutamate transport by applying an innovative, impedance-based, whole-cell assay (xCELLigence). A broad range of GT949 concentrations in a variety of cellular environments were tested in this assay. As expected, no activation of EAAT3 could be detected. Yet, surprisingly, no biological activation of GT949 on EAAT2 could be observed in this assay either. To validate whether the impedance-based assay was not suited to pick up increased glutamate uptake or if the compound might not induce activation in this setup, we performed radioligand uptake assays. Two setups were utilized; a novel method compared to previously published research, and in a reproducible fashion copying the methods used in the existing literature. Nonetheless, activation of neither EAAT2 nor EAAT3 could be observed in these assays. Furthermore, no evidence of GT949 binding or stabilization of purified EAAT2 could be observed in a thermal shift assay. To conclude, based on experimental evidence in the present study GT949 requires specific assay conditions, which are difficult to reproduce, and the compound cannot simply be classified as an activator of EAAT2 based on the presented evidence. Hence, further research is required to develop the tools needed to identify new EAAT modulators and use their potential as a therapeutic target.

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“…3). EAAT2a is the full-length variant and is mainly detected in the human brain, whereas EAAT2b and EAAT2c present distinctive C-terminal domains whose functions are still unknown (Alijanpour et al 2023). Several transcription factor-binding sequences have been identified in the promoter of EAAT2, including NF-κB, N-myc, CREB, NFAT, Sp1 and EGR.…”

Section: -Introductionmentioning

confidence: 99%

Regulatory drugs of glutamate transporter 1 (EAAT2/GLT-1) expression and activity: role in quenching oxidative damage

Domínguez-González,

Romero-Llopis,

Roldán-Lázaro

et al. 2024

Redox Experimental Medicine

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L-glutamate is one of the major neurotransmitters in the CNS, directly and indirectly involved in numerous brain functions. In several neurodegenerative diseases, it has been observed that an excess of extracellular glutamate overstimulates glutamate receptors, leading to exacerbated neuronal excitation in a process of excitotoxicity and oxidative damage that promotes neuronal death. A number of L-glutamate transporters have been identified in the membrane of neurons and astrocytes. They are responsible for the reuptake of glutamate released into the synaptic cleft after excitatory neurotransmission concomitantly regulating the extracellular concentration of glutamate, protecting neurons from its excitotoxic action. Among all of them, literature highlights Glutamate Transporter 1, known as Excitatory Amino Acid Transporter type 2 (EAAT2) in humans and Glutamate Transporter type 1 (GLT-1) in rodents, also known as solute carrier family 1 member 2 (SLC1A2). It is the predominant glutamate transporter in the brain and ensures the majority of L-glutamate reuptake. Decreased expression of this transporter along with increased levels of oxidative stress have been observed in several chronic and acute neurodegenerative disorders. For this reason, the use of drugs capable of both, increasing the expression of Glutamate Transporter 1 and mitigating oxidative damage, has been proposed as an effective therapeutic strategy for these pathologies. We present in this work an overview of the main drugs displaying such a double effect.

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The role of excitatory amino acid transporter 2 (EAAT2) in epilepsy and other neurological disorders

Cited by 6 publications

References 150 publications

Latest advances in mechanisms of epileptic activity in Alzheimer’s disease and dementia with Lewy Bodies

Latest advances in mechanisms of epileptic activity in Alzheimer’s disease and dementia with Lewy Bodies

Still in Search for an EAAT Activator: GT949 Does Not Activate EAAT2, nor EAAT3 in Impedance and Radioligand Uptake Assays

Regulatory drugs of glutamate transporter 1 (EAAT2/GLT-1) expression and activity: role in quenching oxidative damage

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