title: Persistent phosphorylation by protein kinase Mzeta maintains late-phase long-term potentiation.
abstract: Protein kinase Mzeta (PKMzeta), an autonomously active atypical PKC isoform, is both necessary and sufficient for enhanced synaptic transmission during long-term potentiation (LTP) maintenance. LTP, however, evolves through several temporal phases, which may be mediated by distinct molecular mechanisms of potentiation. Here, we determined the specific phase of LTP maintained by PKMzeta. Using a selective, cell-permeable zeta-pseudosubstrate inhibitor at concentrations that block potentiation produced by postsynaptic perfusion of PKMzeta, we inhibited PKMzeta activity at various times after tetanization of Schaffer collateral/commissural-CA1 synapses. Inhibition of PKMzeta did not affect baseline AMPA receptor-mediated synaptic transmission or an early phase of LTP. In contrast, the inhibitor reversed established LTP when applied 1, 3, or 5 h after tetanic stimulation. Control nontetanized pathways within the hippocampal slices were unaffected. An inactive scrambled version of the peptide had no effect on LTP. Thus, persistent, increased phosphorylation by PKMzeta specifically maintains the late phase of LTP.
authors.affiliation: Department of Physiology, State University of New York Downstate Medical Center, Brooklyn, New York 11203, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Serrano
authors.forename: Yudong
authors.initials: Y
authors.lastname: Yao
authors.forename: Todd Charlton
authors.initials: TC
authors.lastname: Sacktor
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D002352:Carrier Proteins / Q000494:pharmacology; D004640:Emetine / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D007527:Isoenzymes / Q000502:physiology*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008969:Molecular Sequence Data; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity
chemical_list: D002352:Carrier Proteins; D007527:Isoenzymes; D010446:Peptide Fragments; D000841:Anisomycin; D011493:Protein Kinase C; C504730:protein kinase M zeta, rat; D004640:Emetine
references.citation: Learn Mem. 1994 May-Jun;1(1):74-82
references.pmid: 10467587
references.citation: Learn Mem. 1999 Sep-Oct;6(5):399-416
references.pmid: 10541462
references.citation: J Neurosci. 2000 Feb 1;20(3):969-76
references.pmid: 10648701
references.citation: J Neurosci. 2000 Jun 15;20(12):4446-51
references.pmid: 10844013
references.citation: Hippocampus. 2000;10(5):542-54
references.pmid: 11075824
references.citation: Hippocampus. 2000;10(5):555-60
references.pmid: 11075825
references.citation: J Neurophysiol. 2001 Apr;85(4):1368-76
references.pmid: 11287461
references.citation: Annu Rev Neurosci. 2001;24:1071-89
references.pmid: 11520928
references.citation: Chem Rev. 2001 Aug;101(8):2353-64
references.pmid: 11749377
references.citation: Nat Neurosci. 2002 Apr;5(4):295-6
references.pmid: 11914719
references.citation: J Neurophysiol. 2002 Jun;87(6):2770-7
references.pmid: 12037179
references.citation: Nat Neurosci. 2003 Mar;6(3):231-42
references.pmid: 12577062
references.citation: Philos Trans R Soc Lond B Biol Sci. 2003 Apr 29;358(1432):745-8
references.pmid: 12740121
references.citation: J Biol Chem. 2003 Oct 10;278(41):40305-16
references.pmid: 12857744
references.citation: Cell. 2004 Feb 6;116(3):467-79
references.pmid: 15016380
references.citation: Neuron. 2004 May 27;42(4):567-80
references.pmid: 15157419
references.citation: J Biol Chem. 2004 Dec 10;279(50):52613-22
references.pmid: 15371429
references.citation: Science. 2004 Oct 15;306(5695):487-91
references.pmid: 15486301
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 23;101(47):16665-70
references.pmid: 15542587
references.citation: J Neurochem. 2004 Dec;91(6):1344-57
references.pmid: 15584911
references.citation: Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6467-71
references.pmid: 1677768
references.citation: J Neurosci. 1990 Oct;10(10):3353-60
references.pmid: 2213144
references.citation: Science. 1989 Aug 25;245(4920):862-6
references.pmid: 2549638
references.citation: Neuroscience. 1989;28(3):519-26
references.pmid: 2710327
references.citation: Nature. 1986 May 8-14;321(6066):175-7
references.pmid: 3010137
references.citation: Brain Res. 1988 Jun 14;452(1-2):57-65
references.pmid: 3401749
references.citation: Annu Rev Neurosci. 1987;10:459-76
references.pmid: 3551762
references.citation: Nature. 1987 Jul 30-Aug 5;328(6129):426-9
references.pmid: 3614346
references.citation: J Biol Chem. 1983 Jan 25;258(2):1156-64
references.pmid: 6296071
references.citation: J Neurosci. 1984 Dec;4(12):3080-8
references.pmid: 6502226
references.citation: Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):11175-9
references.pmid: 7479960
references.citation: Trends Neurosci. 1994 Oct;17(10):406-12
references.pmid: 7530878
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 1993 Jul;348(1):1-6
references.pmid: 7690906
references.citation: Science. 1994 Aug 19;265(5175):1104-7
references.pmid: 8066450
references.citation: Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8310-3
references.pmid: 8104334
references.citation: Neuroreport. 1993 Jun;4(6):712-4
references.pmid: 8347813
references.citation: Proc Natl Acad Sci U S A. 1993 Sep 15;90(18):8342-6
references.pmid: 8378304
references.citation: Science. 1993 Jun 11;260(5114):1661-4
references.pmid: 8389057
references.citation: Brain Res. 1993 Apr 23;609(1-2):1-8
references.pmid: 8389645
references.citation: Nature. 1993 Jan 7;361(6407):31-9
references.pmid: 8421494
references.citation: J Neurosci. 1996 Apr 15;16(8):2444-51
references.pmid: 8786421
references.citation: Nature. 1997 Feb 6;385(6616):533-6
references.pmid: 9020359
references.citation: Cell. 1997 Mar 7;88(5):615-26
references.pmid: 9054501
references.citation: J Neurosci. 1997 Jul 15;17(14):5357-65
references.pmid: 9204920
references.citation: J Biol Chem. 1997 Aug 1;272(31):19103-6
references.pmid: 9235897
references.citation: J Neurophysiol. 1997 Nov;78(5):2682-92
references.pmid: 9356418
references.citation: J Biol Chem. 1998 Feb 20;273(8):4516-22
references.pmid: 9468506
references.citation: J Biol Chem. 1998 Nov 13;273(46):30306-15
references.pmid: 9804792
references.citation: J Neurophysiol. 1998 Nov;80(5):2797-800
references.pmid: 9819284