Zinc signaling in the life and death of neurons

Abstract

ZnT3 (SLC30a3), a zinc transporter, packages zinc into glutamatergic synaptic vesicles, imparting the metal with potential neurotransmitter-like properties. In fact, zinc is released from nerve terminals in an activity-dependent fashion and interacts with neurotransmitter receptors, influencing their function. This is most notably the case for the NMDA receptor, where synaptically released zinc can effectively regulate ion channel function. Critically, synaptically released zinc also directly activates a receptor (mZnR/GPR39) whose primary ligand is the metal itself, regulating neuronal excitation. In essence, then, zinc is a neurotransmitter. Zinc is also, in and of itself, a critical and ubiquitous second messenger. Intracellular zinc in neurons can be liberated from metal-binding proteins, such as metallothionein, via redox-regulated processes. The liberated zinc, in turn, can activate both pro-survival and pro-cell death signaling cascades, the latter of which are associated with the injury-mediated enhancement of functional Kv2.1 potassium channels in the cell membrane, leading to the cell death-promoting loss of cytoplasmic potassium. It is thus not altogether surprising that cellular zinc is tightly regulated through the presence of metal-binding proteins and multiple zinc transporters, many of which are covered in detail elsewhere in this book. This rich array of zinc signaling processes in neurons clearly point to the many vital and critical roles the metal plays in brain function and dysfunction.