TY - JOUR T1 - A Novel View on the Role of Intracellular Tails in Surface Delivery of the Potassium-Chloride Cotransporter KCC2 JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0055-17.2017 SP - ENEURO.0055-17.2017 AU - Perrine Friedel AU - Anastasia Ludwig AU - Christophe Pellegrino AU - Morgane Agez AU - Anass Jawhari AU - Claudio Rivera AU - Igor Medina Y1 - 2017/07/12 UR - http://www.eneuro.org/content/early/2017/07/12/ENEURO.0055-17.2017.1.abstract N2 - A plethora of neurological disorders are associated with alterations in the expression and localization of the potassium-chloride co-transporter type 2 (KCC2), making KCC2 a critical player in neuronal function and an attractive target for therapeutic treatment. The activity of KCC2 is determined primarily by the rates of its surface insertion and internalization. Currently the domains of KCC2 dictating its trafficking and endocytosis are unknown. Here, using live-cell immunolabelling and biotinylation of KCC2 proteins expressed either in murine neuroblastoma N2a cells, human embryonic kidney 293 cells or primary cultures of rat hippocampal neurons, we identified a novel role for the intracellular N- and C-termini in differentially regulating KCC2 surface expression. We report that the N-terminus is required for KCC2 insertion into the plasma membrane, while the C-terminus is critical for the membrane stability of KCC2. Our results provide novel insights into the structure-function role of specific KCC2 domains and open perspectives in exploring structural organization of this protein.Significance Statement The neuronal potassium-chloride co-transporter KCC2 is critically involved in numerous neurologic disorders. However, the structural components that regulate KCC2 activity remain to be elucidated. Here, we describe novel and differential roles for the intracellular amino- and carboxy-terminal domains of KCC2 that dictate its plasmalemmal insertion and surface stabilization. Our findings challenge the current view on the structure-function role of the cytoplasmic regions of KCC2 and propose new targets in the search for therapeutic treatments. ER -