Intracellular zinc inhibits KCC2 transporter activity

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Abstract
Potassium-chloride co-transporter 2 (KCC2) activity is known to be attenuated by neural injury. Hershfinkel et al. show that KCC2 activity is inhibited by intracellular free zinc, a component of neuronal injury signaling pathways. Oxygen-glucose deprivation results in attenuation of KCC2 activity that is reversible by intracellular zinc chelation. We found that K+/Cl− co-transporter 2 (KCC2) activity, monitored with wide-field fluorescence, was inhibited by intracellular Zn2+, a major component of neuronal injury. Zn2+-mediated KCC2 inhibition produced a depolarizing shift of GABAA reversal potentials in rat cortical neurons. Moreover, oxygen-glucose deprivation attenuated KCC2 activity in a Zn2+-dependent manner. The link between Zn2+ and KCC2 activity provides a previously unknown target for neuroprotection and may be important in activity-dependent regulation of inhibitory synaptic transmission.