A ZIP3/ZnT1-mediated zinc cycle is essential for synaptic zinc regulation of NMDA receptors

Zinc is a nutritionally important metal with critical roles in normal brain function. Although many actions of zinc affecting nerve cells (neurons) have been described, we do not fully understand yet how the metal is finely regulated to modulate neuronal activity. In a previously NSF/BSF-funded project, we posited that zinc can move or translocate from one side of the synapse (the “presynaptic” side), the main point of communication in the brain, to the other (the “postsynaptic” side). Once inside the postsynaptic cell, zinc rapidly exits, this time near its main target, a protein called the NMDA receptor, inhibiting, and thus finely tuning its function. In those studies, we identified the main player mediating the postsynaptic efflux of zinc, the so-called ZnT1 transporter. However, how zinc entered the postsynaptic cell remained undefined. In the project outlined in the present proposal, we hypothesize that not only the zinc importer ZIP3 is the main route of zinc influx, but that ZIP3 and ZnT1 form a functional complex and mediate what we define here as the “zinc cycle.” That is, zinc derived from presynaptic nerve cells during synaptic activity, rapidly enters postsynaptic cells via ZIP3, and then rapidly exits via ZnT1, which is near its desired target. Hence, this project is expected to elucidate a previously unrecognized physiological process, mediated by ZIP/ZnT transporters, to finely localize zinc and regulate neuronal signaling.