PMID- 24744726
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20140418
LR  - 20220408
IS  - 1663-3563 (Print)
IS  - 1663-3563 (Electronic)
IS  - 1663-3563 (Linking)
VI  - 6
DP  - 2014
TI  - Postsynaptic localization of PSD-95 is regulated by all three pathways downstream 
      of TrkB signaling.
PG  - 6
LID - 10.3389/fnsyn.2014.00006 [doi]
LID - 6
AB  - Brain-derived neurotrophic factor (BDNF) and its receptor TrkB regulate synaptic 
      plasticity. TrkB triggers three downstream signaling pathways; 
      Phosphatidylinositol 3-kinase (PI3K), Phospholipase Cgamma (PLCgamma) and Mitogen 
      activated protein kinases/Extracellular signal-regulated kinases (MAPK/ERK). We 
      previously showed two distinct mechanisms whereby BDNF-TrkB pathway controls 
      trafficking of PSD-95, which is the major scaffold at excitatory synapses and is 
      critical for synapse maturation. BDNF activates the PI3K-Akt pathway and 
      regulates synaptic delivery of PSD-95 via vesicular transport (Yoshii and 
      Constantine-Paton, 2007). BDNF-TrkB signaling also triggers PSD-95 palmitoylation 
      and its transport to synapses through the phosphorylation of the palmitoylation 
      enzyme ZDHHC8 by a protein kinase C (PKC; Yoshii etal., 2011). The second study 
      used PKC inhibitors chelerythrine as well as a synthetic zeta inhibitory peptide 
      (ZIP) which was originally designed to block the brain-specific PKC isoform 
      protein kinase Mvarpi (PKMvarpi). However, recent studies raise concerns about 
      specificity of ZIP. Here, we assessed the contribution of TrkB and its three 
      downstream pathways to the synaptic distribution of endogenous PSD-95 in cultured 
      neurons using chemical and genetic interventions. We confirmed that TrkB, PLC, 
      and PI3K were critical for the postsynaptic distribution of PSD-95. Furthermore, 
      suppression of MAPK/ERK also disrupted PSD-95 expression. Next, we examined the 
      contribution of PKC. While both chelerythrine and ZIP suppressed the postsynaptic 
      localization of PSD-95, RNA interference for PKMvarpi did not have a significant 
      effect. This result suggests that the ZIP peptide, widely used as the "specific" 
      PKMvarpi antagonist by many investigators may block a PKC variant other than PKMvarpi 
      such as PKClambda/iota. Our results indicate that TrkB regulates postsynaptic 
      localization of PSD-95 through all three downstream pathways, but also recommend 
      further work to identify other PKC variants that regulate palmitoylation and 
      synaptic localization of PSD-95.
FAU - Yoshii, Akira
AU  - Yoshii A
AD  - Department of Anatomy and Cell Biology, University of Illinois at Chicago 
      Chicago, IL, USA ; McGovern Institute for Brain Research, Massachusetts Institute 
      of Technology Cambridge, MA, USA ; Constantine-Paton Laboratory, Department of 
      Brain and Cognitive Science, McGovern Institute for Brain Research, Massachusetts 
      Institute of Technology Cambridge, MA USA.
FAU - Constantine-Paton, Martha
AU  - Constantine-Paton M
AD  - McGovern Institute for Brain Research, Massachusetts Institute of Technology 
      Cambridge, MA, USA ; Constantine-Paton Laboratory, Department of Brain and 
      Cognitive Science, McGovern Institute for Brain Research, Massachusetts Institute 
      of Technology Cambridge, MA USA ; Department of Biology, McGovern Institute for 
      Brain Research, Massachusetts Institute of Technology Cambridge, MA, USA.
LA  - eng
GR  - R01 EY006039/EY/NEI NIH HHS/United States
GR  - R01 EY014074/EY/NEI NIH HHS/United States
PT  - Journal Article
DEP - 20140331
PL  - Switzerland
TA  - Front Synaptic Neurosci
JT  - Frontiers in synaptic neuroscience
JID - 101548972
PMC - PMC3978359
OTO - NOTNLM
OT  - BDNF
OT  - MAP kinase
OT  - PI-3 kinase
OT  - PKMvarpi
OT  - PSD-95
OT  - TrkB
OT  - protein kinase C
OT  - synapse formation
EDAT- 2014/04/20 06:00
MHDA- 2014/04/20 06:01
PMCR- 2014/01/01
CRDT- 2014/04/19 06:00
PHST- 2014/01/10 00:00 [received]
PHST- 2014/03/10 00:00 [accepted]
PHST- 2014/04/19 06:00 [entrez]
PHST- 2014/04/20 06:00 [pubmed]
PHST- 2014/04/20 06:01 [medline]
PHST- 2014/01/01 00:00 [pmc-release]
AID - 10.3389/fnsyn.2014.00006 [doi]
PST - epublish
SO  - Front Synaptic Neurosci. 2014 Mar 31;6:6. doi: 10.3389/fnsyn.2014.00006. 
      eCollection 2014.