Protein kinase C promotes N-methyl-D-aspartate (NMDA) receptor trafficking by indirectly triggering calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation.
ABSTRACT Regulation of neuronal NMDA receptor (NMDAR) is critical in synaptic transmission and plasticity. Protein kinase C (PKC) promotes NMDAR trafficking to the cell surface via interaction with NMDAR-associated proteins (NAPs). Little is known, however, about the NAPs that are critical to PKC-induced NMDAR trafficking. Here, we showed that calcium/calmodulin-dependent protein kinase II (CaMKII) could be a NAP that mediates the potentiation of NMDAR trafficking by PKC. PKC activation promoted the level of autophosphorylated CaMKII and increased association with NMDARs, accompanied by functional NMDAR insertion, at postsynaptic sites. This potentiation, along with PKC-induced long term potentiation of the AMPA receptor-mediated response, was abolished by CaMKII antagonist or by disturbing the interaction between CaMKII and NR2A or NR2B. Further mutual occlusion experiments demonstrated that PKC and CaMKII share a common signaling pathway in the potentiation of NMDAR trafficking and long-term potentiation (LTP) induction. Our results revealed that PKC promotes NMDA receptor trafficking and induces synaptic plasticity through indirectly triggering CaMKII autophosphorylation and subsequent increased association with NMDARs.
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ABSTRACT: Active calcium/calmodulin-dependent protein kinase II (CaMKII) has been reported to take a critical role in the induction of long-term potentiation (LTP). Changes in CaMKII activity were detected in various ischemia models. It is tempting to know whether and how CaMKII takes a role in NMDA receptor (NMDAR)-mediated postischemic long-term potentiation (NMDA i-LTP). Here, we monitored changes in NMDAR-mediated field excitatory postsynaptic potentials (NMDA fEPSPs) at different time points following ischemia onset in vitro oxygen and glucose deprivation (OGD) ischemia model. We found that 10 min OGD treatment induced significant i-LTP in NMDA fEPSPs, whereas shorter (3 min) or longer (25 min) OGD treatment failed to induce prominent NMDA i-LTP. CaMKII activity or CaMKII autophosphorylation displays a similar bifurcated trend at different time points following onset of ischemia both in vitro OGD or in vivo photothrombotic lesion (PT) models, suggesting a correlation of increased CaMKII activity or CaMKII autophosphorylation with NMDA i-LTP. Disturbing the association between CaMKII and GluN2B subunit of NMDARs with short cell-permeable peptides Tat-GluN2B reversed NMDA i-LTP induced by OGD treatment. The results provide support to a notion that increased interaction between NMDAR and CaMKII following ischemia-induced increased CaMKII activity and autophosphorylation is essential for induction of NMDA i-LTP.Neural Plasticity 03/2014; 2014:827161. DOI:10.1155/2014/827161 · 3.60 Impact Factor
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ABSTRACT: Glycine can persistently potentiate or depress AMPA responses through differential actions on two binding sites: NMDA and glycine receptors. Whether glycine can induce long-lasting modifications in NMDA responses, however, remains unknown. Here, we report that glycine induces long-term potentiation (LTP) or long-term depression (LTD) of NMDA responses (Gly-LTPNMDA or Gly-LTDNMDA) in a dose-dependent manner in hippocampal CA1 neurons. These modifications of NMDA responses depend on NMDAR activation. In addition, the induction of Gly-LTPNMDA requires binding of glycine with NMDARs, while Gly-LTDNMDA requires that glycine bind with both sites on NMDARs and GlyRs. Moreover, activity-dependent exocytosis and endocytosis of postsynaptic NMDARs underlie glycine-induced bidirectional modification of NMDA EPSCs. Thus, we conclude that glycine at different levels induces bidirectional plasticity of NMDA responses through differentially regulating NMDA receptor trafficking. Our present findings reveal important functions of the two glycine binding sites in gating the direction of synaptic plasticity in NMDA responses.Journal of Biological Chemistry 09/2014; DOI:10.1074/jbc.M114.570630 · 4.60 Impact Factor
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ABSTRACT: The P2X3 receptor plays a vital role in sensory processing and transmission. The assembly and trafficking of the P2X3 receptor are important for its function in primary sensory neurons. As an important inflammation mediator, ATP is released from different cell types around primary sensory neurons, especially under pathological pain conditions. Here, we show that α, β-MeATP dramatically promoted membrane delivery of the P2X3 receptor both in HEK293T cells expressing recombinant P2X3 receptor and in rat primary sensory neurons. α, β-MeATP induced P2X3 receptor-mediated Ca(2+) influx, which further activated Ca(2+)/calmodulin-dependent protein kinase IIα (CaMKIIα). The N terminus of the P2X3 receptor was responsible for CaMKIIα binding, whereas Thr(388) in the C terminus was phosphorylated by CaMKIIα. Thr(388) phosphorylation increased P2X3 receptor binding to caveolin-1. Caveolin-1 knockdown abrogated the α, β-MeATP-induced membrane insertion of the P2X3 receptor. Moreover, α, β-MeATP drove the CaMKIIα-mediated membrane coinsertion of the P2X2 receptor with the P2X3 receptor. The increased P2X3 receptors on the cell membrane that are due to Thr(388) phosphorylation facilitated P2X3 receptor-mediated signal transduction. Together, our data indicate that CaMKIIα and caveolin-1 cooperate to drive ligand-induced membrane delivery of the P2X3 receptor and may provide a mechanism of P2X3 receptor sensitization in pain development.Journal of Molecular Cell Biology 04/2014; 6(2):140-53. DOI:10.1093/jmcb/mju011 · 8.43 Impact Factor