Excitatory amino acid transporters: recent insights into molecular mechanisms, novel modes of modulation and new therapeutic possibilities

Jensen, Anders A.; Fahlke, Christoph; Bjørn‐Yoshimoto, Walden E.; Bunch, Lennart

doi:10.1016/j.coph.2014.10.008

Cited by 78 publications

(60 citation statements)

References 59 publications

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“…It is also noteworthy that current symptomatic relief for AD is provided by memantine, a metabotropic glutamate receptor antagonist. Therefore the astrocyte-specific EAATs offer an intriguing therapeutic target (68)(69)(70) for manipulating excessive glutamate levels as described in AD.…”

Section: Relevance To Alzheimer's Diseasementioning

confidence: 99%

Astrocytic transporters in Alzheimer's disease

Ugbode

Whalley

et al. 2017

Biochemical Journal

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Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at an early stage in neurological diseases, including Alzheimer's disease (AD). These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease-modifying therapies for AD, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of AD. A small number of the 400 transporter superfamilies are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in AD. Here, we review the current evidence for six astrocytic transporter subfamilies involved in AD, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling AD.

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Section: Relevance To Alzheimer's Diseasementioning

confidence: 99%

Astrocytic transporters in Alzheimer's disease

Ugbode

Whalley

et al. 2017

Biochemical Journal

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“…Most of the other studies have been focusing on EAAT2/GLT1; this should not surprise as this transporter is not only responsible for much of GluT in brain tissue (perhaps 90 %, [8]; recent review: [95]) but also because it is, as discussed above, the EAAT most often related to neurological and mental diseases [reviews: 5,7,8,75]. For example, the mechanisms of action of the antibiotic ceftriaxone that has been used to upregulate EAAT2/GLT1 in animal experiments and tested in human trials as a potential therapeutic agent for amyotrophic lateral sclerosis [87][88][89], have been investigated in great detail; ceftriaxone seems to upregulate EAAT2/GLT1 via the transcription factor NFjB signalling pathway [96].…”

Section: Epigenetics and Transcription Regulation Of Eaatsmentioning

confidence: 97%

GLAST But Not Least—Distribution, Function, Genetics and Epigenetics of l-Glutamate Transport in Brain—Focus on GLAST/EAAT1

et al. 2015

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Synaptically released L-glutamate, the most important excitatory neurotransmitter in the CNS, is removed from extracellular space by fast and efficient transport mediated by several transporters; the most abundant ones are EAAT1/GLAST and EAAT2/GLT1. The review first summarizes their location, functions and basic characteristics. We then look at genetics and epigenetics of EAAT1/GLAST and EAAT2/GLT1 and perform in silico analyses of their promoter regions. There is one CpG island in SLC1A2 (EAAT2/GLT1) gene and none in SLC1A3 (EAAT1/GLAST) suggesting that DNA methylation is not the most important epigenetic mechanism regulating EAAT1/GLAST levels in brain. There are targets for specific miRNA in SLC1A2 (EAAT2/GLT1) gene. We also note that while defects in EAAT2/GLT1 have been associated with various pathological states including chronic neurodegenerative diseases, very little is known on possible contributions of defective or dysfunctional EAAT1/GLAST to any specific brain disease. Finally, we review evidence of EAAT1/GLAST involvement in mechanisms of brain response to alcoholism and present some preliminary data showing that ethanol, at concentrations which may be reached following heavy drinking, can have an effect on the distribution of EAAT1/GLAST in cultured astrocytes; the effect is blocked by baclofen, a GABA-B receptor agonist and a drug potentially useful in the treatment of alcoholism. We argue that more research effort should be focused on EAAT1/GLAST, particularly in relation to alcoholism and drug addiction.

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“…This is underscored by the fact that the neurotransmitter being modulated by hyperforin is mediated by neurotransmitter transporters of different classes. The serotonin, norepinephrine, dopamine, and GABA transporter belong to the SLC6 gene family; the L-glutamate transporter belongs to the class of SLC1 plasma membrane transporters (Scimemi 2014;Jensen et al 2015;Lin et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Hyperforin: To Be or Not to Be an Activator of TRPC(6)

Friedland

Harteneck

2015

Reviews of Physiology, Biochemistry and Pharmacology

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Meantime, it is well accepted that hyperforin, the chemical instable phloroglucinol derivative of Hypericum perforatum, St. John's wort, is the pharmacophore of St. John's wort extracts. With the decline of this scientific discussion, another controversial aspect has been arisen, the question regarding the underlying mechanism leading to the pharmacological profile of the plant extract used in therapy of depression. We will summarize the different concepts described for hyperforin's antidepressive activity. Starting with unspecific protein-independent mechanisms due to changes in pH, we will summarize data of protein-based concepts beginning with concepts based on involvement of a variety of proteins and will finally present concepts based on the modulation of a single protein.

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Excitatory amino acid transporters: recent insights into molecular mechanisms, novel modes of modulation and new therapeutic possibilities

Cited by 78 publications

References 59 publications

Astrocytic transporters in Alzheimer's disease

Astrocytic transporters in Alzheimer's disease

GLAST But Not Least—Distribution, Function, Genetics and Epigenetics of l-Glutamate Transport in Brain—Focus on GLAST/EAAT1

Hyperforin: To Be or Not to Be an Activator of TRPC(6)

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