Glutamate Transporter Dysfunction and Neuronal Death

Ganel, Raquelli; Rothstein, Jeffery D.

doi:10.1007/978-3-662-08022-1_15

Cited by 5 publications

(8 citation statements)

References 130 publications

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“…Glutamate efflux from astrocytes can also occur by other routes. The role of astrocyte glutamate transport in disease states is now receiving intensive study (Ganel and Rothstein, 1999), and a role for disturbed transport has been proposed for neuronal injury in ischemia (Seki et al, 1999;Rossi et al, 2000), amyotrophic lateral sclerosis (Rothstein et al, 1990(Rothstein et al, , 1995Trotti et al, 1999), acquired immunodeficiency syndrome (Vesce et al, 1997;Pappas et al, 1998;Yu et al, 1998), epilepsy (Rothstein et al, 1996;Tanaka et al, 1997), and hepatic encephalopathy (Hazell and Norenberg, 1997;Chan and Butterworth, 1999).…”

Section: Discussionmentioning

confidence: 99%

Astrocyte glutamate transport: Review of properties, regulation, and physiological functions

Anderson

Swanson

2000

Glia

1,075

603

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Section: Discussionmentioning

confidence: 99%

Astrocyte glutamate transport: Review of properties, regulation, and physiological functions

Anderson

Swanson

2000

Glia

1,075

603

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“…The family of glutamate transporters has two primary subclasses: the excitatory amino acid transporter (EAAT) family and vesicular glutamate transporter (VGLUT) family. The EAATs are membrane‐bound secondary transporters similar to ion channels with five subtypes named EAAT1‐5 ( SLC1A3 , SLC1A2 , SLC1A1 , SLC1A6 , SLC1A7 ) . These transporters have essential roles in the regulation of glutamate concentrations across the cellular membranes .…”

Section: What Is Known and Objectivementioning

confidence: 99%

“…These transporters have essential roles in the regulation of glutamate concentrations across the cellular membranes . They quickly remove glutamate from the extracellular space following the action potential, in order to terminate synaptic transmission . Accumulation of glutamate is toxic to neurons as it triggers a number of biochemical cascades in a process called excitotoxicity …”

Section: What Is Known and Objectivementioning

confidence: 99%

“…The EAATs are membrane-bound secondary transporters similar to ion channels with five subtypes named EAAT1-5 (SLC1A3, SLC1A2, SLC1A1, SLC1A6, SLC1A7). 17 These transporters have essential roles in the regulation of glutamate concentrations across the cellular membranes. 18 They quickly remove glutamate from the extracellular space following the action potential, in order to terminate synaptic transmission.…”

Section: What Is K Nown and Objec Tivementioning

confidence: 99%

“…18 They quickly remove glutamate from the extracellular space following the action potential, in order to terminate synaptic transmission. 17,19 Accumulation of glutamate is toxic to neurons as it triggers a number of biochemical cascades in a process called excitotoxicity. 20 SLC1A1 encodes a neuronal glutamate transporter and is a promising candidate gene for obsessive-compulsive disorder (OCD).…”

Section: What Is K Nown and Objec Tivementioning

confidence: 99%

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Genetic and pharmacogenetic study of glutamate transporter (SLC1A1) in Iranian patients with obsessive-compulsive disorder

et al. 2018

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Summary What is known and objective Obsessive‐compulsive disorder (OCD) is a chronic neuropsychiatric disorder. Selective serotonin reuptake inhibitors (SSRIs) are the first line of medication for OCD treatment; however, 40%‐60% of patients with OCD do not respond to SSRIs adequately. There are growing pieces of evidence which suggest a significant role for the glutamatergic system in the genesis of OCD and its consequent treatment. In the present study, we aimed to assess the association of SLC1A1 polymorphisms (rs301430, rs2228622 and rs3780413) with OCD and its clinical characteristics, as well as the importance of these SNPs in the response of OCD patients to SSRI pharmacotherapy. Methods Sample study consisted of 243 OCD cases and 221 control subjects. Patients were treated 12 weeks with fluvoxamine (daily dose: 150‐300 mg). Based on the reduction in obsessive and compulsive severity scores using Y‐BOCS severity scale, patients were classified as responders, non‐responders and refractory. A total of 239, 228 and 215 patients were genotyped for rs301430, rs2228622 and rs3780413, respectively, by the means of PCR‐RFLP. Results and discussion No association was detected between SLC1A1 SNPs and OCD, except an association between the familial form of the disease in males with rs2228622 (P = 0.033). The results of pharmacogenetic studies revealed the associations of two SLC1A1 SNPs, rs2228622 (P = 0.031) and rs3780413 (P = 0.008), with treatment response. What is new and conclusion Results of the current study suggest a role for the glutamate transporter in OCD treatment response with SSRIs which should encourage researchers to further investigate the importance of glutamate transporter in OCD pharmacogenetics.

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Role of Excitatory Amino Acid Transporter‐2 (EAAT2) and glutamate in neurodegeneration: Opportunities for developing novel therapeutics

Kim

Lee

Kegelman

et al. 2011

Journal Cellular Physiology

328

262

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Glutamate is an essential excitatory neurotransmitter regulating brain functions. Excitatory amino acid transporter (EAAT)-2 is one of the major glutamate transporters expressed predominantly in astroglial cells and is responsible for 90% of total glutamate uptake. Glutamate transporters tightly regulate glutamate concentration in the synaptic cleft. Dysfunction of EAAT2 and accumulation of excessive extracellular glutamate has been implicated in the development of several neurodegenerative diseases including Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Analysis of the 2.5-kb human EAAT2 promoter showed that NF-κB is an important regulator of EAAT2 expression in astrocytes. Screening of approximately 1,040 FDA-approved compounds and nutritionals led to the discovery that many β-lactam antibiotics are transcriptional activators of EAAT2 resulting in increased EAAT2 protein levels. Treatment of animals with ceftriaxone (CEF), a β-lactam antibiotic, led to an increase of EAAT2 expression and glutamate transport activity in the brain. CEF has neuroprotective effects in both in vitro and in vivo models based on its ability to inhibit neuronal cell death by preventing glutamate excitotoxicity. CEF increases EAAT2 transcription in primary human fetal astrocytes (PHFA) through the NF-κB signaling pathway. The NF-κB binding site at −272 position was critical in CEF-mediated EAAT2 protein induction. These studies emphasize the importance of transcriptional regulation in controlling glutamate levels in the brain. They also emphasize the potential utility of the EAAT2 promoter for developing both low and high throughput screening assays to identify novel small molecule regulators of glutamate transport with potential to ameliorate pathological changes occurring during and causing neurodegeneration.

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Glutamate Transporter Dysfunction and Neuronal Death

Cited by 5 publications

References 130 publications

Astrocyte glutamate transport: Review of properties, regulation, and physiological functions

Astrocyte glutamate transport: Review of properties, regulation, and physiological functions

Genetic and pharmacogenetic study of glutamate transporter (SLC1A1) in Iranian patients with obsessive-compulsive disorder

Role of Excitatory Amino Acid Transporter‐2 (EAAT2) and glutamate in neurodegeneration: Opportunities for developing novel therapeutics

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