Zn2+ reduction induces neuronal death with changes in voltage-gated potassium and sodium channel currents

Abstract

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 Zn²⁺ chelator, to establish a model of free Zn²⁺ deficiency in neurons. The effects of TPEN-mediated free Zn²⁺ ion reduction on neuronal viability and on the performance of voltage-gated sodium channels (VGSCs) and potassium channels (Kvs) were assessed. Free Zn²⁺ deficiency 1) markedly reduced the neuronal survival rate, 2) reduced the peak amplitude of I_Na, 3) shifted the I_Na 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 Zn²⁺ deficiency by TPEN notably enhanced the peak amplitude of transient outward K⁺ currents (I_A) and delayed rectifier K⁺ currents (I_K), as well as caused hyperpolarization and depolarization directional shifts in their steady-state activation curves, respectively. Zn²⁺ supplementation reversed the effects induced by TPEN. Our results indicate that free Zn²⁺ deficiency causes neuronal damage and alters the dynamic characteristics of VGSC and Kv currents. Thus, neuronal injury caused by free Zn²⁺ deficiency may correlate with its modulation of the electrophysiological properties of VGSCs and Kvs.

Keywords: Free Zn(2+) deficiency; Neuronal injury; TPEN; Voltage-gated potassium channel current; Voltage-gated sodium channel current.