title: Plk2 attachment to NSF induces homeostatic removal of GluA2 during chronic overexcitation.
abstract: Trafficking of AMPA receptors (AMPARs) is important for many forms of synaptic plasticity. However, the link between activity and resulting synaptic alterations is not fully understood. We identified a direct interaction between N-ethylmaleimide-sensitive fusion protein (NSF), an ATPase involved in membrane fusion events and stabilization of surface AMPARs, and Polo-like kinase- 2 (Plk2), an activity-inducible kinase that homeostatically decreases excitatory synapse number and strength. Plk2 disrupted the interaction of NSF with the GluA2 subunit of AMPARs, promoting extensive loss of surface GluA2 in rat hippocampal neurons, greater association of GluA2 with adaptor proteins PICK1 and GRIP1, and decreased synaptic AMPAR current. Plk2 engagement of NSF, but not Plk2 kinase activity, was required for this mechanism and occurred through a motif in the Plk2 protein that was independent of the canonical polo box interaction sites. These data reveal that heightened synaptic activity, acting through Plk2, leads to homeostatic decreases in surface AMPAR expression via the direct dissociation of NSF from GluA2.
authors.affiliation: Department of Pharmacology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Evers
authors.forename: Jose A
authors.initials: JA
authors.lastname: Matta
authors.forename: Hyang-Sook
authors.initials: HS
authors.lastname: Hoe
authors.forename: Devin
authors.initials: D
authors.lastname: Zarkowsky
authors.forename: Sang Hyoung
authors.initials: SH
authors.lastname: Lee
authors.forename: John T
authors.initials: JT
authors.lastname: Isaac
authors.forename: Daniel T S
authors.initials: DT
authors.lastname: Pak
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D020816:Amino Acid Motifs / Q000235:genetics / Q000502:physiology; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003598:Cytoskeletal Proteins; D004622:Embryo, Mammalian; D004705:Endocytosis / Q000187:drug effects / Q000235:genetics; D018756:GABA Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology; D006706:Homeostasis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins; D018613:Microscopy, Confocal / Q000379:methods; D052066:N-Ethylmaleimide-Sensitive Proteins / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010852:Picrotoxin / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014162:Transfection / Q000379:methods
chemical_list: D000255:Adenosine Triphosphate; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D018756:GABA Antagonists; D049452:Green Fluorescent Proteins; D047908:Intracellular Signaling Peptides and Proteins; D052066:N-Ethylmaleimide-Sensitive Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010852:Picrotoxin; D017346:Protein Serine-Threonine Kinases; D018091:Receptors, AMPA; C491308:Grip1 protein, rat; C498298:PICK1 protein, rat; C530504:Plk2 protein, rat; C104722:glutamate receptor ionotropic, AMPA 2
references.citation: J Biol Chem. 2008 Oct 24;283(43):29424-32
references.pmid: 18723513
references.citation: J Neurosci. 2007 Dec 12;27(50):13903-8
references.pmid: 18077702
references.citation: Neuron. 2002 Mar 28;34(1):53-67
references.pmid: 11931741
references.citation: Neuron. 1999 Oct;24(2):389-99
references.pmid: 10571232
references.citation: Neuron. 1998 Aug;21(2):393-400
references.pmid: 9728920
references.citation: J Neurosci. 2001 Aug 1;21(15):5417-28
references.pmid: 11466413
references.citation: Mol Cell Neurosci. 2008 Jun;38(2):189-202
references.pmid: 18417360
references.citation: J Neurosci. 2000 Oct 1;20(19):7258-67
references.pmid: 11007883
references.citation: J Neurosci. 2008 Jul 30;28(31):7820-7
references.pmid: 18667614
references.citation: Mol Cell Neurosci. 2005 Apr;28(4):650-60
references.pmid: 15797712
references.citation: Neuron. 2005 Mar 24;45(6):903-15
references.pmid: 15797551
references.citation: J Neurosci. 2006 May 17;26(20):5309-19
references.pmid: 16707783
references.citation: Nat Neurosci. 2006 May;9(5):602-4
references.pmid: 16582904
references.citation: Neuron. 1999 Jun;23(2):365-76
references.pmid: 10399941
references.citation: J Cell Biol. 2005 May 9;169(3):399-404
references.pmid: 15883194
references.citation: Curr Opin Neurobiol. 2007 Jun;17(3):318-24
references.pmid: 17451937
references.citation: Mol Cell Biol. 1992 Sep;12(9):4164-9
references.pmid: 1508211
references.citation: Proc Natl Acad Sci U S A. 2002 May 14;99(10):7096-101
references.pmid: 12011465
references.citation: Neuron. 2003 Jul 3;39(1):163-76
references.pmid: 12848940
references.citation: Cell. 2001 Jun 29;105(7):825-8
references.pmid: 11439178
references.citation: Cell. 2001 May 4;105(3):331-43
references.pmid: 11348590
references.citation: Neuron. 2000 Nov;28(2):499-510
references.pmid: 11144359
references.citation: Neuron. 1996 Nov;17(5):945-56
references.pmid: 8938126
references.citation: Ann N Y Acad Sci. 1999 Apr 30;868:535-40
references.pmid: 10414331
references.citation: Neuron. 1999 Nov;24(3):649-58
references.pmid: 10595516
references.citation: Proc Natl Acad Sci U S A. 2008 Jan 22;105(3):1038-43
references.pmid: 18195348
references.citation: Neuron. 2005 May 19;46(4):533-40
references.pmid: 15944123
references.citation: Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9301-6
references.pmid: 9689075
references.citation: J Biol Chem. 2002 Oct 25;277(43):40901-10
references.pmid: 12130635
references.citation: Neuron. 2000 Dec;28(3):873-86
references.pmid: 11163273
references.citation: Neuropharmacology. 2007 Jan;52(1):156-75
references.pmid: 16949624
references.citation: Cell. 2003 Oct 3;115(1):83-95
references.pmid: 14532005
references.citation: Neuron. 1998 Jul;21(1):99-110
references.pmid: 9697855
references.citation: Neuron. 2000 Aug;27(2):313-25
references.pmid: 10985351
references.citation: Biochem J. 1999 Apr 15;339 ( Pt 2):435-42
references.pmid: 10191277
references.citation: Neuron. 2002 Nov 14;36(4):661-74
references.pmid: 12441055
references.citation: Neuron. 2009 Apr 30;62(2):254-68
references.pmid: 19409270
references.citation: Neuron. 1998 Jul;21(1):87-97
references.pmid: 9697854
references.citation: Science. 2003 Nov 21;302(5649):1368-73
references.pmid: 14576440
references.citation: FEBS Lett. 2007 May 22;581(11):2140-9
references.pmid: 17397838
references.citation: Neuron. 2006 Nov 9;52(3):475-84
references.pmid: 17088213
references.citation: J Neurosci. 1996 Mar 15;16(6):1982-9
references.pmid: 8604042
references.citation: J Neurosci. 2008 Jun 25;28(26):6583-91
references.pmid: 18579731
references.citation: J Neurosci. 2002 May 1;22(9):3493-503
references.pmid: 11978826
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11725-30
references.pmid: 11573007
references.citation: Neuron. 2008 May 22;58(4):571-83
references.pmid: 18498738
references.citation: J Neurosci. 2009 May 20;29(20):6479-89
references.pmid: 19458219
references.citation: J Neurosci. 2004 Jun 9;24(23):5381-90
references.pmid: 15190111
references.citation: Neuron. 2001 Aug 2;31(2):289-303
references.pmid: 11502259
references.citation: EMBO J. 1999 Oct 15;18(20):5528-39
references.pmid: 10523297