Gabra3, encoding the α3 -subunit of the GABAA receptor, is a gene located on chromosome Xq28. The GABAA receptor is a ligand-gated ion channel that mediates fast inhibitory neurotransmission in the central nervous system, and Gabra3 is involved in regulating GABA-evoked anion currents. It is associated with multiple biological processes and diseases, and genetic models can be valuable for studying its functions.

In cancer, high Gabra3 protein expression in lung adenocarcinoma is positively correlated with disease stage, lymphatic metastasis status, and poor patient survival. Gabra3 promotes lymphatic metastasis by inducing MMP-2 and MMP-9 expression via the JNK/AP-1 signaling pathway [1]. In breast cancer, Gabra3 activates the AKT pathway to promote cell migration, invasion, and metastasis, while an A-to-I RNA-edited form suppresses these processes [2]. In pancreatic cancer, miR-92b-3p acts as a tumor suppressor by targeting Gabra3, and its overexpression suppresses Gabra3, inactivating oncogenic pathways like AKT/mTOR and JNK [4]. In triple-negative breast cancer, miR-92b inhibits cells' epithelial-mesenchymal transition (EMT) by targeting Gabra3, and low miR-92b or high Gabra3 predicts poor prognosis [5]. In glioma, reduced RNA editing of Gabra3 favors glioma migration and invasion, and edited Gabra3 inhibits these processes [6]. In addition, rare loss-of-function variants in Gabra3 increase the risk of a combination of epilepsy, intellectual disability/developmental delay, and dysmorphic features, presenting in some pedigrees with an X-linked inheritance pattern [3].

In conclusion, Gabra3 is involved in multiple biological processes with a significant impact on various diseases, especially cancer. The use of gene knockout or other loss-of-function models in these studies has revealed its role in promoting cancer metastasis and its potential as a therapeutic target. In addition, its association with epilepsy-related disorders further emphasizes its importance in understanding disease mechanisms.