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Ischemia-Induced Post-Translational Modifications of GLT-1 Mediate Aberrant Trafficking and Impaired Glutamate Uptake
Journal article   Open access   Peer reviewed

Ischemia-Induced Post-Translational Modifications of GLT-1 Mediate Aberrant Trafficking and Impaired Glutamate Uptake

Simran Kaur Gill, Katelyn Louise Reeb, Max Kroll, Ole V Mortensen and Andréia C K Fontana
Journal of neurochemistry, v 170(6), e70497
Jun 2026
DOI: https://doi.org/10.1111/jnc.70497
PMID: 42299780
Featured in Collection :   Research Supported by Drexel Libraries' OA Programs
url
https://doi.org/10.1111/jnc.70497View
Published, Version of Record (VoR) Open Access via Drexel Libraries Read and Publish Program 2026 Open CC BY V4.0

Abstract

Animals Astrocytes - metabolism Brain Ischemia - metabolism Cells, Cultured Excitatory Amino Acid Transporter 2 - genetics Excitatory Amino Acid Transporter 2 - metabolism Glutamic Acid - metabolism Hippocampus - metabolism Protein Processing, Post-Translational - physiology Protein Transport - physiology Rats Rats, Sprague-Dawley Ubiquitination
Glutamate transporters are essential for maintaining CNS homeostasis by clearing extracellular glutamate following synaptic transmission. Dysregulation of these transporters contributes to glutamate-mediated excitotoxicity across numerous neurological disorders, including ischemic stroke, underscoring their potential as therapeutic targets. However, the regulatory response of these transporters following ischemic insult remains poorly defined. In this study, using a model of oxygen-glucose deprivation in primary rat glial cultures, we report aberrant trafficking of the astrocytic glutamate transporter GLT-1 following ischemic insult. This response is characterized by increased transporter internalization and degradation, accompanied by reduced glutamate uptake capacity. Focusing on post-translational modifications (PTMs), we found that GLT-1 ubiquitination is markedly increased after ischemic insult and coincides with transporter internalization. Importantly, disrupting this ubiquitination interaction through mutation of C-terminal GLT-1 lysine residues restores GLT-1 surface expression and rescues glutamate uptake capacity through preventing early endosome 1 (EEA1)-mediated internalization. Additionally, we report that inhibition of C-terminal GLT-1 PTMs confers neuroprotection following ischemic insult in organotypic hippocampal brain slices. Together, these findings demonstrate that ischemia-induced dysregulation of GLT-1 trafficking plays a critical role in impaired glutamate clearance and cellular recovery, highlighting GLT-1 ubiquitination as a potential therapeutic target for ischemic injury.

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