Functional investigation of SLC1A2 variants associated with epilepsy

• Published in: Cell death & disease Vol. 13; no. 12; p. 1063
• Main Authors: Qu, Qi, Zhang, Wenlong, Wang, Ji, Mai, Dongmei, Ren, Siqiang, Qu, Shaogang, Zhang, Yunlong
• Format: Journal Article
• Language: English
• Published: England Springer Nature B.V 21.12.2022; Nature Publishing Group UK; Nature Publishing Group
• Subjects: Alzheimer's disease; Amino acids; Animals; Apoptosis; Biological Transport; Calcium - metabolism; Calcium channels; Calcium influx; Calcium Signaling; Cell membranes; Convulsions & seizures; Endoplasmic reticulum; Epilepsy; Epilepsy - genetics; Excitotoxicity; Glutamic Acid - metabolism; Glutamic acid transporter; Health risk assessment; Laboratories; Mice; Mutation; Neurosciences; Orai1 protein; ORAI1 Protein - metabolism; Pathogenesis; Phenotypes; Plasmids; Proteins; STIM1 protein; Stromal Interaction Molecule 1; Therapeutic targets
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-022-05457-6

Epilepsy is a common neurological disorder and glutamate excitotoxicity plays a key role in epileptic pathogenesis. Astrocytic glutamate transporter GLT-1 is responsible for preventing excitotoxicity via clearing extracellular accumulated glutamate. Previously, three variants (G82R, L85P, and P289R) in SLC1A2 (encoding GLT-1) have been clinically reported to be associated with epilepsy. However, the functional validation and underlying mechanism of these GLT-1 variants in epilepsy remain undetermined. In this study, we reported that these disease-linked mutants significantly decrease glutamate uptake, cell membrane expression of the glutamate transporter, and glutamate-elicited current. Additionally, we found that these variants may disturbed stromal-interacting molecule 1 (STIM1)/Orai1-mediated store-operated Ca entry (SOCE) machinery in the endoplasmic reticulum (ER), in which GLT-1 may be a new partner of SOCE. Furthermore, knock-in mice with disease-associated variants showed a hyperactive phenotype accompanied by reduced glutamate transporter expression. Therefore, GLT-1 is a promising and reliable therapeutic target for epilepsy interventions.