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Function of zinc ion (Zn2+) in synaptic biology

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Homeostasis of ionic or labile zinc (Zn2+) in central neurons and at the synapse might be important in a range of physiological and pathological events. Zn2+ may act as a co-transmitter at certain glutamatergic synapses, participate in neuronal signal transduction, modulate memory formation and nociception, or promote neurodegeneration upon brain insults.

Co-labelling of ZnT1 and vesicular Zn2+. (A) Sections of CA1 synapses stained for vesicular Zn2+ (solid arrows) and ZnT1 (solid arrowheads, synaptic; white arrowheads, extrasynaptic).

Co-labelling of ZnT1 and vesicular Zn2+. (A) Sections of CA1 synapses stained for vesicular Zn2+ (solid arrows) and ZnT1 (solid arrowheads, synaptic; white arrowheads, extrasynaptic).

Marked differences in the levels of intracellular Zn2+ are found among cellular compartments owing to the coordinated actions of two families of zinc transporter proteins, Slc30a (ZnT1-10) and Slc39 (ZIP1-14). Whereas ZnTs export Zn2+ away from the cytosol into organelles or the extracellular space, ZIPs shuttle Zn2+ in the opposite direction.

At synapses zinc is normally found in high concentrations. Bound zinc maintains the organization of the postsynaptic density (PSD), where it associates with protein scaffolds such as Shank2/3 and SAP-102. In addition, a subset of excitatory boutons up-take Zn2+ into glutamatergic vesicles via ZnT3. One may expect, therefore, that specific plasma membrane proteins at the postsynaptic site support Zn2+ homeostasis at synapses, but their identity remains elusive. We demonstrate that ZnT1 is a plasma membrane protein that is enriched in hippocampal CA1 postsynaptic densities and in biochemically isolated synaptic membranes. This data suggests that ZnT1 could play a pivotal role in Zn2+ homeostasis at glutamatergic spines.

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