NMDA receptor activity downregulates KCC2 resulting in depolarizing GABA(A) receptor mediated currents

KCC2 is a neuron-specific K(+)-Cl(−) cotransporter that maintains a low intracellular Cl(−) concentration essential for hyperpolarizing inhibition mediated by GABA(A) receptors. Deficits in KCC2 activity occur in disease states associated with pathophysiological glutamate release. However, the mechanisms by which elevated glutamate levels alter KCC2 function are unknown. The phosphorylation of KCC2 residue S940 is known to regulate its surface activity. Here we demonstrated in dissociated rat neurons that NMDA receptor activity and Ca(2+) influx caused the dephosphorylation of S940 leading to a loss of KCC2 function that lasted greater than 20 minutes. PP1 mediated the dephosphorylation events of S940 that coincided with a deficit in hyperpolarizing GABAergic inhibition due to the loss of KCC2 activity. Blocking dephosphorylation of S940 reduced the glutamate-induced downregulation of KCC2 and significantly improved the maintenance of hyperpolarizing GABAergic inhibition. Reducing the downregulation of KCC2 thus has therapeutic potential in the treatment of neurological disorders.