Zinc Transport in the Brain: Routes of Zinc Influx and Efflux in Neurons

Abstract

Studies of the routes of entry and exit for zinc in different tissues and cell types have shown that zinc can use several pathways of exit or entry. In neurons, known pathways include (1) presynaptic release along with glutamate when synaptic vesicles empty their contents into the synaptic cleft, (2) voltage-gated L-type Ca(2+) channels and glutamate-gated channels that provide an entry route when cells are depolarized and that mediate extracellular zinc toxicity and (3) a plasma membrane transporter potentially present in all neurons important for cellular zinc homeostasis. The least understood of these pathways, in terms of mechanism, is the transporter pathway. The kinetics of zinc uptake in cultured neurons under resting conditions are consistent with and suggest the existence of a saturable transporter in the plasma membrane. The proteins responsible for plasma membrane zinc transport have not yet been definitely identified. Likely candidates include two proteins identified by molecular cloning termed zinc transporter 1 and divalent cation transporter DCT1. Both proteins have been shown to be expressed in the brain, but only DCT1 is clearly demonstrated to be a transport protein, whereas zinc transporter 1 may only modulate zinc transport in association with as-yet-unidentified proteins. Understanding the mechanism and neuromodulation of plasma membrane zinc transport will be an important first step toward a complete understanding of neuronal zinc homeostasis.

Vglut1 and ZnT3 co-targeting mechanisms regulate vesicular zinc stores in PC12 cells

“…Bacterial and synaptic vesicle members of the zinctransporter family transport metal by a proton-coupledantiporter mechanism (Chao and Fu, 2004;Colvin et al, 2000a;Colvin et al, 2000b). In bacteria, the antiporter mechanism occurs with a stoichiometry of metal ion to proton close to 1:1 (Chao and Fu, 2004).…”

“…In bacteria, the antiporter mechanism occurs with a stoichiometry of metal ion to proton close to 1:1 (Chao and Fu, 2004). In synaptic vesicles, lumenal zinc accumulation is associated with vesicle alkalinization (Colvin et al, 2000a;Colvin et al, 2000b). Zinc accumulation probably increases the electrical gradient across the synaptic vesicle membrane while increasing the intravesicular pH, thus making the vesicle lumen more positive and favoring vesicular glutamate uptake (Reimer et al, 2001).…”

Cellular and Molecular Pathways of Ischemic Neuronal Death

“…This ischemic neuronal death was prevented by the blockade of Zn 2+ translocation with Ca-EDTA, or the overexpression of metallothionein-1, a Zn 2+ -binding protein (van Lookeren et al, 1999). Zn 2+ ions enter into target cells through voltage-gated calcium channels (VGCC), NMDA, or AMPA/kainate glutamate receptors that are permeable to Ca 2+ , Na + /Ca 2+ exchanger, or Zn 2+ transporter (Freund and Reddig, 1994;Koh and Choi, 1994;Sensi et al, 1997;Sensi et al, 1999;Colvin et al, 2000). The entry and accumulation of Zn 2+ into neurons result in the transient generation of reactive oxygen species that mediate latent neuronal death .…”

Zinc Inhibition of cAMP Signaling

“…Passive influx through the neuronal membrane has been demonstrated to occur when extracellular levels of Zn 2ϩ are elevated, e.g. when Zn 2ϩ is added to the cell culture medium or when Zn 2ϩ is released from presynaptic vesicles (31). However, experiments using cultured neuronal cells have also demonstrated that Zn 2ϩ uptake can be stimulated upon activation of voltage-gated Ca 2ϩ or NMDA channels, for example (1)(2)(3)32).…”