%0 Journal Article
%T Postsynaptic localization of PSD-95 is regulated by all three pathways downstream of TrkB signaling
%A Akira Yoshii
%A Martha Constantine-Paton
%J Frontiers in Synaptic Neuroscience
%D 2014
%I Frontiers Media
%R 10.3389/fnsyn.2014.00006
%X Brain-derived neurotrophic factor (BDNF) and its receptor TrkB regulate synaptic plasticity. TrkB triggers three downstream signaling pathways; Phosphatidylinositol 3-kinase (PI3K), Phospholipase C¦Ã (PLC¦Ã) 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 et al., 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 M¦Æ (PKM¦Æ). 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 PKM¦Æ did not have a significant effect. This result suggests that the ZIP peptide, widely used as the ¡°specific¡± PKM¦Æ antagonist by many investigators may block a PKC variant other than PKM¦Æ such as PKC¦Ë/¦É. 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.
%K synapse formation
%K BDNF
%K TrkB
%K PSD-95
%K PKM¦Æ
%K protein kinase C
%K MAP kinase
%K PI-3 kinase
%U http://www.frontiersin.org/Journal/10.3389/fnsyn.2014.00006/abstract