Slc12a5, encoding K+-Cl- cotransporter 2 (KCC2), is the main Cl- extruder of neurons. It renders the proper inhibitory function of neurotransmitters like γ-aminobutyric acid (GABA) and glycine, thus maintaining the excitation-inhibition balance in the nervous system. Posttranslational modifications such as phosphorylation and glycosylation regulate KCC2 functions [1].

Loss-of-function variants of human SLC12A5 have pathogenic potential. For example, in epilepsy, causative mutations in SLC12A5 have been found in patients, with these variant KCC2 showing impaired Cl- extruding functions [1,7]. In glioblastoma multiforme, SLC12A5 is deficient in tumors while enriched in normal neural tissues and may serve as a novel biomarker [2]. In hepatocellular carcinoma, high SLC12A5 expression promotes tumor growth and ferroptosis resistance by inducing ER stress and changing cystine transport [3]. It also has oncogenic roles in bladder urothelial carcinoma, ovarian carcinoma, and breast cancer, promoting tumor progression through various mechanisms [4,5,6].

In conclusion, Slc12a5 is crucial for maintaining the inhibitory function of neurotransmitters in neurons. Research on Slc12a5, especially through studying its loss-of-function variants, has revealed its significant roles in multiple neurological and cancer-related diseases, providing potential directions for diagnosis, prognosis, and treatment.