title: Tissue plasminogen activator alters intracellular sequestration of zinc through interaction with the transporter ZIP4.
abstract: 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.
authors.affiliation: Program in Molecular and Cellular Pharmacology, Stony Brook University, Stony Brook, New York 11794-8651, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Emmetsberger
authors.forename: Martine M
authors.initials: MM
authors.lastname: Mirrione
authors.forename: Chun
authors.initials: C
authors.lastname: Zhou
authors.forename: Monica
authors.initials: M
authors.lastname: Fernandez-Monreal
authors.forename: Mustafa M
authors.initials: MM
authors.lastname: Siddiq
authors.forename: Kyungmin
authors.initials: K
authors.lastname: Ji
authors.forename: Stella E
authors.initials: SE
authors.lastname: Tsirka
mesh_terms: 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*
chemical_list: D027682:Cation Transport Proteins; D009498:Neurotoxins; C477530:Slc39a4 protein, mouse; D010959:Tissue Plasminogen Activator; D015032:Zinc
references.citation: J Neurosci Res. 2009 Nov 1;87(14):3221-30
references.pmid: 19530166
references.citation: Anal Biochem. 1988 Jul;172(1):210-8
references.pmid: 3189765
references.citation: Trends Mol Med. 2009 Mar;15(3):101-11
references.pmid: 19246244
references.citation: Brain Res. 1986 Oct 22;385(2):291-9
references.pmid: 3779393
references.citation: Annu Rev Neurosci. 1998;21:347-75
references.pmid: 9530500
references.citation: J Struct Biol. 2006 Jul;155(1):2-11
references.pmid: 16495082
references.citation: Trends Pharmacol Sci. 2000 Oct;21(10):395-401
references.pmid: 11050320
references.citation: Epilepsia. 2000;41 Suppl 6:S96-9
references.pmid: 10999528
references.citation: Brain Res. 2001 Mar 23;895(1-2):25-32
references.pmid: 11259756
references.citation: Epilepsia. 1986 May-Jun;27(3):183-8
references.pmid: 3698933
references.citation: Hum Mol Genet. 2004 Mar 1;13(5):563-71
references.pmid: 14709598
references.citation: Am J Physiol Heart Circ Physiol. 2000 Sep;279(3):H1346-54
references.pmid: 10993802
references.citation: J Neurochem. 2001 Aug;78(3):600-10
references.pmid: 11483663
references.citation: J Neurosci Res. 2005 Aug 15;81(4):581-8
references.pmid: 15948190
references.citation: J Neurosci. 2000 Jun 1;20(11):RC79
references.pmid: 10807937
references.citation: Bone. 2005 Sep;37(3):296-304
references.pmid: 16005272
references.citation: Annu Rev Nutr. 2004;24:151-72
references.pmid: 15189117
references.citation: Exp Neurol. 2006 Apr;198(2):285-93
references.pmid: 16443223
references.citation: Biochim Biophys Acta. 2006 Jul;1763(7):711-22
references.pmid: 16675045
references.citation: J Biol Chem. 2007 Mar 9;282(10):6992-7000
references.pmid: 17202136
references.citation: J Neurosci. 2002 May 1;22(9):3352-8
references.pmid: 11978811
references.citation: J Cell Biochem. 1986;32(3):169-78
references.pmid: 3097031
references.citation: J Neurosci Methods. 2006 Jun 30;154(1-2):19-29
references.pmid: 16460810
references.citation: J Neurosci. 2001 Jun 15;21(12):4348-55
references.pmid: 11404420
references.citation: J Neurosci. 2008 Mar 19;28(12):3114-22
references.pmid: 18354014
references.citation: J Biol Chem. 2003 Aug 29;278(35):33474-81
references.pmid: 12801924
references.citation: Biochim Biophys Acta. 2007 Aug;1768(8):1976-90
references.pmid: 17433250
references.citation: J Comp Neurol. 1996 Sep 30;373(4):593-618
references.pmid: 8889946
references.citation: Brain Res. 1988 Apr 19;446(2):383-6
references.pmid: 3370496
references.citation: Biochemistry. 1986 Jul 15;25(14):4033-40
references.pmid: 2943315
references.citation: Nature. 1995 Sep 28;377(6547):340-4
references.pmid: 7566088
references.citation: Mol Neurobiol. 2001 Aug-Dec;24(1-3):99-106
references.pmid: 11831557
references.citation: Curr Biol. 1998 Jan 1;8(1):19-25
references.pmid: 9427623
references.citation: J Recept Signal Transduct Res. 2007;27(2-3):99-111
references.pmid: 17613723
references.citation: Epilepsy Behav. 2001 Feb;2(1):54-60
references.pmid: 12609182
references.citation: J Biol Chem. 2004 Feb 6;279(6):4523-30
references.pmid: 14612438
references.citation: Nature. 1993 Feb 4;361(6411):453-7
references.pmid: 8429885
references.citation: Proc Natl Acad Sci U S A. 2003 May 13;100(10):6157-62
references.pmid: 12724524
references.citation: Amyotroph Lateral Scler. 2007 Jun;8(3):131-43
references.pmid: 17538774
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2247-52
references.pmid: 17283338
references.citation: Science. 2004 Oct 15;306(5695):487-91
references.pmid: 15486301
references.citation: Epilepsy Res Suppl. 1992;7:301-13
references.pmid: 1334669
references.citation: PLoS One. 2008;3(11):e3642
references.pmid: 18985159
references.citation: Neuron. 1993 Jan;10(1):43-9
references.pmid: 7678965
references.citation: Biochim Biophys Acta. 1999 Oct 6;1447(1):125-31
references.pmid: 10500253
references.citation: Mol Cell Neurosci. 2004 Jan;25(1):162-71
references.pmid: 14962749
references.citation: Synapse. 2006 Feb;59(2):119-21
references.pmid: 16320304
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 29;95(20):11975-80
references.pmid: 9751775
references.citation: Nat Biotechnol. 2000 Jun;18(6):655-60
references.pmid: 10835605
references.citation: Epilepsia. 2002;43 Suppl 5:196-202
references.pmid: 12121321
references.citation: Exp Mol Med. 2000 Dec 31;32(4):227-30
references.pmid: 11190275
references.citation: Nat Med. 2001 Jan;7(1):59-64
references.pmid: 11135617
references.citation: J Histochem Cytochem. 2005 Feb;53(2):141-53
references.pmid: 15684327
references.citation: Anal Chem. 1983 May;55(6):921-3
references.pmid: 6349416
references.citation: Science. 1999 Apr 23;284(5414):647-50
references.pmid: 10213688
references.citation: Mol Pharmacol. 2001 May;59(5):981-6
references.pmid: 11306679
references.citation: Brain Res. 2006 Mar 17;1078(1):227-34
references.pmid: 16490181