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.

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