Figure 6.

Proposed mechanism for the synergistic interaction between Zn²⁺ and Cu²⁺ at the synapse. Zn and glutamate accumulate in synaptic vesicles and are released into synaptic clefts during neuronal excitation. Zn²⁺ regulates Ca²⁺ influx through NMDA-type glutamate receptors, modulates neuronal information, and is implicated in the maintenance of synaptic plasticity and memory formation, similar to Ca²⁺. Zn²⁺ enters target neurons via voltage-dependent Ca²⁺ channels, NMDA-type glutamate channels, and Ca²⁺-permeable AMPA/kainate channels. The increased intracellular Zn²⁺ induces ER stress pathways and triggers apoptotic pathways. The ZnT-1 Zn transporter regulates Zn homeostasis and is localized to post-synaptic membranes that express NMDA-type glutamate receptors. Carnosine is released from glial cells into synaptic clefts, and is thought to regulate excess Zn. ZnT-1, zinc transporter 1; ZnT-3, zinc transporter 3; AMPA-R, AMPA-type glutamate receptor; NMDA-R, NMDA-type glutamate receptor; CAR, carnosine.