Redox Regulation of Intracellular Zinc: Molecular Signaling in the Life and Death of Neurons

Zn(2+) has emerged as a major regulator of neuronal physiology, as well as an important signaling agent in neural injury. The intracellular concentration of this metal is tightly regulated through the actions of Zn(2+) transporters and the thiol-rich metal binding protein metallothionein, closely linking the redox status of the cell to cellular availability of Zn(2+). Accordingly, oxidative and nitrosative stress during ischemic injury leads to an accumulation of neuronal free Zn(2+) and the activation of several downstream cell death processes. While this Zn(2+) rise is an established signaling event in neuronal cell death, recent evidence suggests that a transient, sublethal accumulation of free Zn(2+) can also play a critical role in neuroprotective pathways activated during ischemic preconditioning. Thus, redox-sensitive proteins, like metallothioneins, may play a critical role in determining neuronal cell fate by regulating the localization and concentration of intracellular free Zn(2+).