The structural basis of function and regulation of neuronal cotransporters NKCC1 and KCC2.

NKCC and KCC transporters mediate coupled transport of Na++K++Cl− and K++Cl− across the plasma membrane, thus regulating cell Cl− concentration and cell volume and playing critical roles in transepithelial salt and water transport and in neuronal excitability. The function of these transporters has been intensively studied, but a mechanistic understanding has awaited structural studies of the transporters. Here, we present the cryo-electron microscopy (cryo-EM) structures of the two neuronal cation-chloride cotransporters human NKCC1 (SLC12A2) and mouse KCC2 (SLC12A5), along with computational analysis and functional characterization. These structures highlight essential residues in ion transport and allow us to propose mechanisms by which phosphorylation regulates transport activity. Zhang et al. present the cryo-electron microscopy structures of the two neuronal cation-chloride cotransporters human NKCC1 and mouse KCC2, identifying their essential residues for ion transport. This study proposes mechanisms by which phosphorylation regulates the activity of these cation-chloride cotransporters.