Tissue Plasminogen Activator Alters Intracellular Sequestration of Zinc through Interaction with the Transporter ZIP4
Journal of Neuroscience. 2010-05-12; 30(19): 6538-6547
DOI: 10.1523/JNEUROSCI.6250-09.2010
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Glutamatergic neurons contain free zinc packaged into neurotransmitter-loaded
synaptic vesicles. Upon neuronal activation, the vesicular contents are released
into the synaptic space, whereby the zinc modulates activity of postsynaptic
neurons though interactions with receptors, transporters and exchangers. However,
high extracellular concentrations of zinc trigger seizures and are neurotoxic if
substantial amounts of zinc reenter the cells via ion channels and accumulate in
the cytoplasm. Tissue plasminogen activator (tPA), a secreted serine protease, is
also proepileptic and excitotoxic. However, tPA counters zinc toxicity by
promoting zinc import back into the neurons in a sequestered form that is
nontoxic. Here, we identify the zinc influx transporter, ZIP4, as the pathway
through which tPA mediates the zinc uptake. We show that ZIP4 is upregulated
after excitotoxin stimulation of the mouse, male and female, hippocampus. ZIP4
physically interacts with tPA, correlating with an increased intracellular zinc
influx and lysosomal sequestration. Changes in prosurvival signals support the
idea that this sequestration results in neuroprotection. These experiments
identify a mechanism via which neurons use tPA to efficiently neutralize the
toxic effects of excessive concentrations of free zinc.