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FASEB Journal

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Rescue of Epilepsy‐Associated Mutations of the Highly Conserved Glycine Residue 443 in the Human GABA Transporter 1

Published:9 June 2025 DOI: 10.1096/fj.202403159RR
Nikita Shah, Vasylyna Kovalchuk, Rocco Zerlotti, Kim Cole, Andre Bazzone, Harald H. Sitte, Thomas Hummel, Ameya S. Kasture, Sonja Sucic

Abstract

The human γ-aminobutyric acid (GABA) transporter 1 (hGAT-1) plays a pivotal role in synaptic neurotransmission by facilitating the clearance of GABA from the synaptic cleft. Pathogenic mutations in the SLC6A1 gene encoding hGAT-1 have been implicated in a spectrum of neurodevelopmental disorders, including epilepsy, autism spectrum disorder, intellectual disability, and developmental delay. Here, we elucidate the molecular and functional consequences of disease-associated mutations affecting the highly conserved glycine residue at position 443 (G443) in hGAT-1. Through a combination of in vitro biochemical analyses, ion flux assays, and pharmacological profiling in HEK293 cells, alongside in vivo studies in Drosophila melanogaster, we demonstrate that substitutions of G443 to aspartate (G443D) or valine (G443V) result in complete abolishment of GABA transport. This severe impairment stems from distinct disruptions in protein folding and trafficking. In particular, G443V is fully retained in the endoplasmic reticulum (ER), as substantiated by de-glycosylation assays indicating exclusively core-glycosylated protein bands and confocal co-localization with the ER chaperone calnexin. The G443D variant, on the other hand, exhibits partial trafficking to the plasma membrane, confirmed by the presence of maturely glycosylated bands, albeit at significantly reduced expression levels relative to the wild type transporter. Treatment with glycerol and 4-phenylbutyrate (4-PBA) successfully restored both surface expression and GABA uptake activity of the G443 mutants. Our findings highlight the potential of small-molecule chaperones as interventions for ameliorating protein misfolding and functional deficits in hGAT-1-associated pathologies.

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GUVACINE HYDROCHLORIDE 6027-91-4 C6H10ClNO2 123 suppliers $29.00-$1593.90
GUVACINE HYDROCHLORIDE 6027-91-4 C6H10ClNO2 123 suppliers $29.00-$1593.90
GUVACINE HYDROCHLORIDE 6027-91-4 C6H10ClNO2 123 suppliers $29.00-$1593.90
GUVACINE HYDROCHLORIDE 6027-91-4 C6H10ClNO2 123 suppliers $29.00-$1593.90

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