A Zinc—Potassium Continuum in Neuronal Apoptosis

Intraneuronal zinc homeostasis is tightly regulated by a variety of specialized ionic transport mechanisms, metal binding proteins, and organelle com-partmentalization. Dysregulation of these processes by pathophysiological conditions, especially those in which reactive oxygen and nitrogen species (ROS, RNS) have been implicated, is central to the progression of neuronal injury. In addition to disruption of zinc homeostatic mechanisms, a reduction of intracellular ionic strength via enhanced potassium efflux is a critical and perhaps requisite mediator of apoptotic cell death induced by lethal insults to the brain. In this chapter, we describe the manner by which the cellular dysregulation of these two essential ions, zinc and potassium, lies along a signaling continuum leading to the demise of central neurons. By reviewing the current status of the field and presenting new information, we detail the molecular mechanisms linking intracellular zinc liberation to cellular potassium efflux in acute neuronal injury, such as ischemia. The complete characterization of this potentially ubiquitous cell death signaling cascade will likely provide novel therapeutic targets for cerebral ischemia and, possibly, other forms of neurodegeneration.