Persistent phosphorylation by protein kinase Mzeta maintains late-phase long-term potentiation.
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.
Serrano
Peter
P
Department of Physiology, State University of New York Downstate Medical Center, Brooklyn, New York 11203, USA.
Yao
Yudong
Y
Sacktor
Todd Charlton
TC
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
D002352:Carrier Proteins; D007527:Isoenzymes; D010446:Peptide Fragments; D000841:Anisomycin; D011493:Protein Kinase C; C504730:protein kinase M zeta, rat; D004640:Emetine
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