GLT-1 transporter: An effective pharmacological target for various neurological disorders

Soni, Neha; Reddy, Bandugula Venkata; Kumar, Puneet

doi:10.1016/j.pbb.2014.10.001

Cited by 71 publications

(67 citation statements)

References 157 publications

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“…ischemia) will impair the transport process (for review see: Szatkowski and Attwell, 1994;Rossi et al, 2000;Danbolt, 2001;Larsson et al, 2004;Grewer and Rauen, 2005;Tzingounis and Wadiche, 2007). A full discussion about molecular properties and roles of glutamate transporters in disease, however, is beyond the scope of this review as that topic is covered elsewhere (for review see for example: Lipton and Rosenberg, 1994;Danbolt, 2001;Sattler and Rothstein, 2006;Beart and O'Shea, 2007;Sheldon and Robinson, 2007;Bröer and Palacin, 2011;Vandenberg and Ryan, 2013;Karki et al, 2015;Soni et al, 2014;Takahashi et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Neuronal vs glial glutamate uptake: Resolving the conundrum

Danbolt

Furness

Zhou

2016

Neurochemistry International

177

152

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Neither normal brain function nor the pathological processes involved in neurological diseases can be adequately understood without knowledge of the release, uptake and metabolism of glutamate. The reason for this is that glutamate (a) is the most abundant amino acid in the brain, (b) is at the cross-roads between several metabolic pathways, and (c) serves as the major excitatory neurotransmitter. In fact most brain cells express glutamate receptors and are thereby influenced by extracellular glutamate. In agreement, brain cells have powerful uptake systems that constantly remove glutamate from the extracellular fluid and thereby limit receptor activation. It has been clear since the 1970s that both astrocytes and neurons express glutamate transporters. However, the relative contribution of neuronal and glial transporters to the total glutamate uptake activity, however, as well as their functional importance, has been hotly debated ever since. The present short review provides (a) an overview of what we know about neuronal glutamate uptake as well as an historical description of how we got there, and (b) a hypothesis reconciling apparently contradicting observations thereby possibly resolving the paradox. ABBREVIATIONSCre, Cyclization recombinase (Le and Sauer, 2000); EAAC1, glutamate transporter (EAAT3; slc1a1; Kanai and Hediger, 1992; Bjørås et al., 1996); EAAT, excitatory amino acid transporter (synonym to glutamate transporter); GABA, γ-aminobutyric acid; GLAST, rat glutamate transporter (EAAT1; slc1a3; Storck et al., 1992;Tanaka, 1993a); GLT-1, rat glutamate transporter (EAAT2; slc1a2; Pines et al., 1992); GLUL, glutamine synthetase; TBOA, DL-threo-β-benzyloxyaspartate AbstractNeither normal brain function nor the pathological processes involved in neurological diseases can be adequately understood without knowledge of the release, uptake and metabolism of glutamate. The reason for this is that glutamate (a) is the most abundant amino acid in the brain, (b) is at the cross-roads between several metabolic pathways, and (c) serves as the major excitatory neurotransmitter. In fact most brain cells express glutamate receptors and are thereby influenced by extracellular glutamate. In agreement, brain cells have powerful uptake systems that constantly remove glutamate from the extracellular fluid and thereby limit receptor activation. It has been clear since the 1970s that astrocytes and neurons express glutamate transporters. The relative contribution of neuronal and glial transporters to the total glutamate uptake activity, however, as well as their functional importance, has been hotly debated ever since. The present short review provides (a) an overview of what we know about neuronal glutamate uptake as well as an historical description of how we got there, and (b) an hypothesis reconciling apparently contradicting observations thereby possibly resolving the paradox.

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Section: Introductionmentioning

confidence: 99%

Neuronal vs glial glutamate uptake: Resolving the conundrum

Danbolt

Furness

Zhou

2016

Neurochemistry International

177

152

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“…Excitation is modulated by excitatory neurotransmitters and mostly by glutamate [4]. It is generally accepted that the majority of glutamate transport in the CNS, particularly as related to excitatory transmission, is mediated by a group of high-affinity, sodium-dependent, glutamate transporters, thereby terminating the transmitter signal and protecting neurons from an excitotoxic action of glutamate and providing cells throughout the body with glutamate for metabolic purposes [5,6]. Approximately 80% of the glutamate transporters expressed in the hippocampus are GLT-1 [7].…”

Section: Introductionmentioning

confidence: 99%

“…GLT-1b is present to a lesser extent [8]. Relatively little is known about the mechanisms that regulate GLT-1 or the other Na + -dependent glutamate transporters, but it suggests that the expression of GLT-1/EAAT-2 is regulated by transcriptional and/or posttranscriptional processes [6]. It was suggested that malfunctioning of glutamate transporters (GLTs) is one of the main causative factors of hyperexcitation, seizure spread, and neurotoxicity [6,[9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…Relatively little is known about the mechanisms that regulate GLT-1 or the other Na + -dependent glutamate transporters, but it suggests that the expression of GLT-1/EAAT-2 is regulated by transcriptional and/or posttranscriptional processes [6]. It was suggested that malfunctioning of glutamate transporters (GLTs) is one of the main causative factors of hyperexcitation, seizure spread, and neurotoxicity [6,[9][10][11]. Some studies also reported that an increased GLT-1 expression can protect mice against status epilepticus (SE)-induced death, neuropathological changes, and chronic seizure development [12,13].…”

Section: Introductionmentioning

confidence: 99%

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Effect of GLT-1 modulator and P2X7 antagonists alone and in combination in the kindling model of epilepsy in rats

Soni

Koushal

Reddy

et al. 2015

Epilepsy & Behavior

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“…Furthermore, 1 was found to alter EAAT2 gene expression, to enhance glutamate transport in primary human fetal astrocytes, to delay loss of neuronal cells, to increase muscle strength, and to enhance mouse survival in an in vivo model of amyotrophic lateral sclerosis (ALS). 9 The activation of the expression of glial GLT-1 led to an antinociceptive effect in diverse rodent pains comprising neuropathic pain. 10 It was reported that extracellular levels of glutamate were considerably boosted after repeated chemotherapeutic bortezomib administration to rats.…”

Section: ■ Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Novel Neuroprotective Pyridazine Derivatives as Excitatory Amino Acid Transporter 2 (EAAT2) Activators

et al. 2017

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LDN-212320 (3) was found to be a potent EAAT2 activator at a translational level, restoring the normal clearance of glutamate and providing neuronal protection. Since the pharmacologic activation of EAAT2 represents a valuable strategy to relieve neuropathic pain, we synthesized novel activators (4a−f) of EAAT2. Among them 4f, analyzed in comparison with 3 by different paradigms in a rat model of oxaliplatin-induced neuropathic pain, showed the better antihypersensitive profile being able to fully counteract the oxaliplatin-induced neuropathy.

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GLT-1 transporter: An effective pharmacological target for various neurological disorders

Cited by 71 publications

References 157 publications

Neuronal vs glial glutamate uptake: Resolving the conundrum

Neuronal vs glial glutamate uptake: Resolving the conundrum

Effect of GLT-1 modulator and P2X7 antagonists alone and in combination in the kindling model of epilepsy in rats

Synthesis and Biological Evaluation of Novel Neuroprotective Pyridazine Derivatives as Excitatory Amino Acid Transporter 2 (EAAT2) Activators

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