PKM zeta maintains late long-term potentiation by N-ethylmaleimide-sensitive factor/GluR2-dependent trafficking of postsynaptic AMPA receptors.
Although the maintenance mechanism of late long-term potentiation (LTP) is critical for the storage of long-term memory, the expression mechanism of synaptic enhancement during late-LTP is unknown. The autonomously active protein kinase C isoform, protein kinase Mzeta (PKMzeta), is a core molecule maintaining late-LTP. Here we show that PKMzeta maintains late-LTP through persistent N-ethylmaleimide-sensitive factor (NSF)/glutamate receptor subunit 2 (GluR2)-dependent trafficking of AMPA receptors (AMPARs) to the synapse. Intracellular perfusion of PKMzeta into CA1 pyramidal cells causes potentiation of postsynaptic AMPAR responses; this synaptic enhancement is mediated through NSF/GluR2 interactions but not vesicle-associated membrane protein-dependent exocytosis. PKMzeta may act through NSF to release GluR2-containing receptors from a reserve pool held at extrasynaptic sites by protein interacting with C-kinase 1 (PICK1), because disrupting GluR2/PICK1 interactions mimic and occlude PKMzeta-mediated AMPAR potentiation. During LTP maintenance, PKMzeta directs AMPAR trafficking, as measured by NSF/GluR2-dependent increases of GluR2/3-containing receptors in synaptosomal fractions from tetanized slices. Blocking this trafficking mechanism reverses established late-LTP and persistent potentiation at synapses that have undergone synaptic tagging and capture. Thus, PKMzeta maintains late-LTP by persistently modifying NSF/GluR2-dependent AMPAR trafficking to favor receptor insertion into postsynaptic sites.
Yao
Yudong
Y
The Robert F. Furchgott Center for Neural and Behavioral Science, Department of Physiology, State University of New York, Downstate Medical Center, Brooklyn, New York 11203, USA.
Kelly
Matthew Taylor
MT
Sajikumar
Sreedharan
S
Serrano
Peter
P
Tian
Dezhi
D
Bergold
Peter John
PJ
Frey
Julietta Uta
JU
Sacktor
Todd Charlton
TC
D000595:Amino Acid Sequence; D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D007527:Isoenzymes / Q000502:physiology; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D008969:Molecular Sequence Data; D052066:N-Ethylmaleimide-Sensitive Proteins / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000378:metabolism / Q000502:physiology*
D007527:Isoenzymes; D018091:Receptors, AMPA; D011493:Protein Kinase C; C504730:protein kinase M zeta, rat; D052066:N-Ethylmaleimide-Sensitive Proteins; C104722:glutamate receptor ionotropic, AMPA 2