Arundic Acid Increases Expression and Function of Astrocytic Glutamate Transporter EAAT1 Via the ERK, Akt, and NF-κB Pathways

Pratap Karki, Peter Hong, James Johnson, Edward Pajarillo, Deok Soo Son, Michael Aschner, Eunsook Y. Lee

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Glutamate is the major excitatory neurotransmitter in the brain, but excessive synaptic glutamate must be removed to prevent excitotoxic injury and death. Two astrocytic glutamate transporters, excitatory amino acid transporter (EAAT) 1 and 2, play a major role in eliminating excess glutamate from the synapse. Dysregulation of EAAT1 contributes to the pathogenesis of multiple neurological disorders, such as Alzheimer’s disease (AD), ataxia, traumatic brain injuries, and glaucoma. In the present study, we investigated the effect of arundic acid on EAAT1 to determine its efficacy in enhancing the expression and function of EAAT1, and its possible mechanisms of action. The studies were carried out in human astrocyte H4 cells as well as in human primary astrocytes. Our findings show that arundic acid upregulated EAAT1 expression at the transcriptional level by activating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Arundic acid increased astrocytic EAAT1 promoter activity, messenger RNA (mRNA)/protein levels, and glutamate uptake, while pharmacological inhibition of NF-κB or mutation on NF-κB binding sites in the EAAT1 promoter region abrogated these effects. Arundic acid increased NF-κB reporter activity and induced NF-κB nuclear translocation as well as its bindings to the EAAT1 promoter. Furthermore, arundic acid activated the Akt and ERK signaling pathways to enhance EAAT1 mRNA/protein levels. Finally, arundic acid attenuated manganese-induced decrease in EAAT1 expression by inhibiting expression of the transcription factor Ying Yang 1 (YY1). These results demonstrate that arundic acid increases the expression and function of EAAT1 via the Akt, ERK, and NF-κB signaling pathways, and reverses Mn-induced EAAT1 repression by inhibiting the Mn-induced YY1 activation.

Original languageEnglish (US)
Pages (from-to)1-16
Number of pages16
JournalMolecular Neurobiology
DOIs
StateAccepted/In press - Aug 15 2017

Fingerprint

Amino Acid Transport System X-AG
Glutamic Acid
Astrocytes
Excitatory Amino Acid Transporter 2
Excitatory Amino Acid Transporter 1
Messenger RNA
MAP Kinase Signaling System
Ataxia
Manganese
ONO2506
Nervous System Diseases
Genetic Promoter Regions
Glaucoma
Synapses
Neurotransmitter Agents
Alzheimer Disease
Proteins
B-Lymphocytes
Transcription Factors
Binding Sites

Keywords

  • Arundic acid
  • Astrocytes
  • EAAT1
  • Manganese
  • NF-κB

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

Arundic Acid Increases Expression and Function of Astrocytic Glutamate Transporter EAAT1 Via the ERK, Akt, and NF-κB Pathways. / Karki, Pratap; Hong, Peter; Johnson, James; Pajarillo, Edward; Son, Deok Soo; Aschner, Michael; Lee, Eunsook Y.

In: Molecular Neurobiology, 15.08.2017, p. 1-16.

Research output: Contribution to journalArticle

Karki, Pratap ; Hong, Peter ; Johnson, James ; Pajarillo, Edward ; Son, Deok Soo ; Aschner, Michael ; Lee, Eunsook Y. / Arundic Acid Increases Expression and Function of Astrocytic Glutamate Transporter EAAT1 Via the ERK, Akt, and NF-κB Pathways. In: Molecular Neurobiology. 2017 ; pp. 1-16.
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