Transient striatal GLT-1 blockade increases EAAC1 expression, glutamate reuptake, and decreases tyrosine hydroxylase phosphorylation at ser 19

Michael Francis Salvatore, Richard W. Davis, Jennifer C. Arnold, Tanya Chotibut

Research output: Contribution to journalArticleResearchpeer-review

19 Citations (Scopus)

Abstract

Three glutamate transporters, GLT-1, GLAST, and EAAC1, are expressed in striatum. GLT-1 and, to a lesser extent, GLAST are thought to play a primary role in glutamate reuptake and mitigate excitoxicity. Progressive tyrosine hydroxylase (TH) loss seen in Parkinson's disease (PD) is associated with increased extracellular glutamate. Glutamate receptor antagonists reduce nigrostriatal loss in PD models. These observations suggest that excess synaptic glutamate contributes to nigrostriatal neuron loss seen in PD. Decreased GLT-1 expression occurs in neurodegenerative disease and PD models, suggesting decreased GLT-1-mediated glutamate reuptake contributes to excitotoxicity. To determine how transient GLT-1 blockade affects glutamate reuptake dynamics and a Ca 2+-dependent process in nigrostriatal terminals, ser 19 phosphorylation of TH, the GLT-1 inhibitor dihydrokainic acid (DHK) was delivered unilaterally to striatum in vivo and glutamate reuptake was quantified ex vivo in crude synaptosomes 3h later. Ca 2+-influx is associated with excitotoxic conditions. The phosphorylation of TH at ser 19 is Ca 2+-dependent, and a change resulting from GLT-1 blockade may signify the potential for excitotoxicity to nigrostriatal neurons. Synaptosomes from DHK infused striatum had a 43% increase in glutamate reuptake in conjunction with decreased ser 19 TH phosphorylation. Using a novel GLAST inhibitor and DHK, we determined that the GLAST-mediated component of increased glutamate reuptake increased 3-fold with no change in GLAST or GLT-1 protein expression. However, GLT-1 blockade increased EAAC1 protein expression ~20%. Taken together, these results suggest that GLT-1 blockade produces a transient increase in GLAST-mediated reuptake and EAAC1 expression coupled with reduced ser 19 TH phosphorylation. These responses could represent an endogenous defense against excitotoxicity to the nigrostriatal pathway.

Original languageEnglish
Pages (from-to)428-436
Number of pages9
JournalExperimental Neurology
Volume234
Issue number2
DOIs
StatePublished - 1 Apr 2012

Fingerprint

Corpus Striatum
Tyrosine 3-Monooxygenase
Glutamic Acid
Phosphorylation
Parkinson Disease
Synaptosomes
Amino Acid Transport System X-AG
Neurons
Excitatory Amino Acid Antagonists
Neurodegenerative Diseases
Proteins

Keywords

  • EAAC1/EAAT3
  • Excitotoxicity
  • GLAST/EAAT1
  • GLT-1/EAAT2
  • Glutamate
  • Glutathione
  • Nigrostriatal
  • Parkinson's disease
  • Phosphorylation
  • Striatum
  • Tyrosine hydroxylase

Cite this

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title = "Transient striatal GLT-1 blockade increases EAAC1 expression, glutamate reuptake, and decreases tyrosine hydroxylase phosphorylation at ser 19",
abstract = "Three glutamate transporters, GLT-1, GLAST, and EAAC1, are expressed in striatum. GLT-1 and, to a lesser extent, GLAST are thought to play a primary role in glutamate reuptake and mitigate excitoxicity. Progressive tyrosine hydroxylase (TH) loss seen in Parkinson's disease (PD) is associated with increased extracellular glutamate. Glutamate receptor antagonists reduce nigrostriatal loss in PD models. These observations suggest that excess synaptic glutamate contributes to nigrostriatal neuron loss seen in PD. Decreased GLT-1 expression occurs in neurodegenerative disease and PD models, suggesting decreased GLT-1-mediated glutamate reuptake contributes to excitotoxicity. To determine how transient GLT-1 blockade affects glutamate reuptake dynamics and a Ca 2+-dependent process in nigrostriatal terminals, ser 19 phosphorylation of TH, the GLT-1 inhibitor dihydrokainic acid (DHK) was delivered unilaterally to striatum in vivo and glutamate reuptake was quantified ex vivo in crude synaptosomes 3h later. Ca 2+-influx is associated with excitotoxic conditions. The phosphorylation of TH at ser 19 is Ca 2+-dependent, and a change resulting from GLT-1 blockade may signify the potential for excitotoxicity to nigrostriatal neurons. Synaptosomes from DHK infused striatum had a 43{\%} increase in glutamate reuptake in conjunction with decreased ser 19 TH phosphorylation. Using a novel GLAST inhibitor and DHK, we determined that the GLAST-mediated component of increased glutamate reuptake increased 3-fold with no change in GLAST or GLT-1 protein expression. However, GLT-1 blockade increased EAAC1 protein expression ~20{\%}. Taken together, these results suggest that GLT-1 blockade produces a transient increase in GLAST-mediated reuptake and EAAC1 expression coupled with reduced ser 19 TH phosphorylation. These responses could represent an endogenous defense against excitotoxicity to the nigrostriatal pathway.",
keywords = "EAAC1/EAAT3, Excitotoxicity, GLAST/EAAT1, GLT-1/EAAT2, Glutamate, Glutathione, Nigrostriatal, Parkinson's disease, Phosphorylation, Striatum, Tyrosine hydroxylase",
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Transient striatal GLT-1 blockade increases EAAC1 expression, glutamate reuptake, and decreases tyrosine hydroxylase phosphorylation at ser 19 . / Salvatore, Michael Francis; Davis, Richard W.; Arnold, Jennifer C.; Chotibut, Tanya.

In: Experimental Neurology, Vol. 234, No. 2, 01.04.2012, p. 428-436.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Transient striatal GLT-1 blockade increases EAAC1 expression, glutamate reuptake, and decreases tyrosine hydroxylase phosphorylation at ser 19

AU - Salvatore, Michael Francis

AU - Davis, Richard W.

AU - Arnold, Jennifer C.

AU - Chotibut, Tanya

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AB - Three glutamate transporters, GLT-1, GLAST, and EAAC1, are expressed in striatum. GLT-1 and, to a lesser extent, GLAST are thought to play a primary role in glutamate reuptake and mitigate excitoxicity. Progressive tyrosine hydroxylase (TH) loss seen in Parkinson's disease (PD) is associated with increased extracellular glutamate. Glutamate receptor antagonists reduce nigrostriatal loss in PD models. These observations suggest that excess synaptic glutamate contributes to nigrostriatal neuron loss seen in PD. Decreased GLT-1 expression occurs in neurodegenerative disease and PD models, suggesting decreased GLT-1-mediated glutamate reuptake contributes to excitotoxicity. To determine how transient GLT-1 blockade affects glutamate reuptake dynamics and a Ca 2+-dependent process in nigrostriatal terminals, ser 19 phosphorylation of TH, the GLT-1 inhibitor dihydrokainic acid (DHK) was delivered unilaterally to striatum in vivo and glutamate reuptake was quantified ex vivo in crude synaptosomes 3h later. Ca 2+-influx is associated with excitotoxic conditions. The phosphorylation of TH at ser 19 is Ca 2+-dependent, and a change resulting from GLT-1 blockade may signify the potential for excitotoxicity to nigrostriatal neurons. Synaptosomes from DHK infused striatum had a 43% increase in glutamate reuptake in conjunction with decreased ser 19 TH phosphorylation. Using a novel GLAST inhibitor and DHK, we determined that the GLAST-mediated component of increased glutamate reuptake increased 3-fold with no change in GLAST or GLT-1 protein expression. However, GLT-1 blockade increased EAAC1 protein expression ~20%. Taken together, these results suggest that GLT-1 blockade produces a transient increase in GLAST-mediated reuptake and EAAC1 expression coupled with reduced ser 19 TH phosphorylation. These responses could represent an endogenous defense against excitotoxicity to the nigrostriatal pathway.

KW - EAAC1/EAAT3

KW - Excitotoxicity

KW - GLAST/EAAT1

KW - GLT-1/EAAT2

KW - Glutamate

KW - Glutathione

KW - Nigrostriatal

KW - Parkinson's disease

KW - Phosphorylation

KW - Striatum

KW - Tyrosine hydroxylase

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DO - 10.1016/j.expneurol.2012.01.012

M3 - Article

VL - 234

SP - 428

EP - 436

JO - Experimental Neurology

JF - Experimental Neurology

SN - 0014-4886

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