Zn(2+) reduction induces neuronal death with changes in voltage-gated potassium and sodium channel currents.

In the present study, cultured rat primary neurons were exposed to a medium containing N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), a specific cell membrane-permeant Zn(2+) chelator, to establish a model of free Zn(2+) deficiency in neurons. The effects of TPEN-mediated free Zn(2+) ion reduction on neuronal viability and on the performance of voltage-gated sodium channels (VGSCs) and potassium channels (Kvs) were assessed. Free Zn(2+) deficiency 1) markedly reduced the neuronal survival rate, 2) reduced the peak amplitude of INa, 3) shifted the INa activation curve towards depolarization, 4) modulated the sensitivity of sodium channel voltage-dependent inactivation to a depolarization voltage, and 5) increased the time course of recovery from sodium channel inactivation. In addition, free Zn(2+) deficiency by TPEN notably enhanced the peak amplitude of transient outward K(+) currents (IA) and delayed rectifier K(+) currents (IK), as well as caused hyperpolarization and depolarization directional shifts in their steady-state activation curves, respectively. Zn(2+) supplementation reversed the effects induced by TPEN. Our results indicate that free Zn(2+) deficiency causes neuronal damage and alters the dynamic characteristics of VGSC and Kv currents. Thus, neuronal injury caused by free Zn(2+) deficiency may correlate with its modulation of the electrophysiological properties of VGSCs and Kvs.