Regulated degradation of KCC2, a potassium-chloride co-transporter required for synaptic transmission and neurodevelopment.

Neuronal function requires fine-tuned and coordinated activity of several ion channels and transporters. One member of this ensemble is the KCC2 potassium-chloride cotransporter. Because KCC2 expression is required for GABA-dependent inhibitory synaptic transmission, mutations in the gene encoding KCC2 (SLC12A5) have been linked to several diseases that also arise from defects in GABA signaling, including epilepsy, schizophrenia, and autism spectrum disorders. Although characterization of the corresponding mutant proteins is ongoing, KCC2 mutants may reside at the cell surface but lack function, they may remain trapped intracellularly and are thus unable to function at the cell surface, or they may be readily degraded. In this article, we summarize these data and emphasize the importance of protein degradation and protease activity during KCC2 quality control, i.e. the pathway that ensures only properly folded and mature KCC2 can traffic to and function at the cell surface. We also highlight how proteolysis regulates the amount of active KCC2 at the cell surface, i.e. KCC2 quantity control. Finally, because previously unidentified KCC2 mutants are continuously being discovered, we discuss the use of predictive pathogenicity algorithms to provide researchers with information on potential disease outcomes.