Mutations in the GABA transporter GAT-1 (SLC6A1) are known to cause developmental and epileptic disorders but not all mutations are created equal. A new study takes a deep dive into two epilepsy-linked substitutions at glycine 443 (G443), a residue conserved across the entire SLC6 family.

The variants G443D and G443V were both found to abolish GABA uptake, but through different mechanisms. G443V caused complete endoplasmic reticulum (ER) retention of the transporter, while G443D allowed some trafficking to the cell surface, though with severely compromised function.

Using a combination of radioligand uptake, SSM-based electrophysiology (SURFE²R), and structural modeling, the team demonstrated that these folding-defective variants can be rescued by pharmacochaperones. In particular, 4-phenylbutyrate (4-PBA) restored surface expression and function of the G443V variant, while glycerol showed partial rescue of G443D.

Importantly, the rescue effects were not just seen in vitro. In Drosophila models expressing the human G443V variant, treatment with 4-PBA enhanced protein expression in astrocytes and reduced heat-induced seizure-like episodes, suggesting translational potential for pharmacochaperoning in GAT-1-related epilepsy.

This work not only highlights the distinct consequences of G443 substitutions but also underscores the promise of small molecule chaperones in correcting misfolded transporter proteins implicated in neurological disease.

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Find the full article here: Rescue of Epilepsy‐Associated Mutations of the Highly Conserved Glycine Residue 443 in the Human GABA Transporter 1

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