Tissue plasminogen activator alters intracellular sequestration of zinc through interaction with the transporter ZIP4.
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.
Emmetsberger
Jaime
J
Program in Molecular and Cellular Pharmacology, Stony Brook University, Stony Brook, New York 11794-8651, USA.
Mirrione
Martine M
MM
Zhou
Chun
C
Fernandez-Monreal
Monica
M
Siddiq
Mustafa M
MM
Ji
Kyungmin
K
Tsirka
Stella E
SE
D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000633:toxicity; D010959:Tissue Plasminogen Activator / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*
D027682:Cation Transport Proteins; D009498:Neurotoxins; C477530:Slc39a4 protein, mouse; D010959:Tissue Plasminogen Activator; D015032:Zinc
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