Protein Kinase C Promotes N-Methyl-D-aspartate (NMDA) Receptor Trafficking by Indirectly Triggering Calcium/Calmodulin-dependent Protein Kinase II (CaMKII) Autophosphorylation

Department of Neurobiology, Nanjing Medical University, Nanjing, Jiangsu Province 210029, China.
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2011; 286(28):25187-200. DOI: 10.1074/jbc.M110.192708
Source: PubMed


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.

    • "in the cerebral cortex induced by tDCS[Islam et al., 1994]. The PKC g is engaged in the phosphorylation of AMPA receptors[McDonald et al., 2001;Nanou and ElManira, 2010;Yan et al., 2011]that are related to the early stages of long-term potentiation (LTP)—that is online learningSantos et al., 2007]. Thus, tDCS could induce larger gains in performance from a single session of application[Liebetanz et al., 2002;Nitsche et al., 2003Nitsche et al., , 2004Ragert et al., 2008]by exerting a more profound effect on the phosphorylation of AMPA receptors . "
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    ABSTRACT: We investigated the effect of repeated delivery of anodal transcranial direct current stimulation (tDCS) on somatosensory performance and long-term learning. Over the course of five days, tDCS was applied to the primary somatosensory cortex (S1) by means of neuronavigation employing magnetencephalography (MEG). Compared to its sham application, tDCS promoted tactile learning by reducing the two-point discrimination threshold assessed by the grating orientation task (GOT) primarily by affecting intersessional changes in performance. These results were accompanied by alterations in the neurofunctional organization of the brain, as revealed by functional magnetic resonance imaging conducted prior to the study, at the fifth day of tDCS delivery and four weeks after the last application of tDCS. A decrease in activation at the primary site of anodal tDCS delivery in the left S1 along retention of superior tactile acuity was observed at follow-up four weeks after the application of tDCS. Thus, we demonstrate long-term effects that repeated tDCS imposes on somatosensory functioning. This is the first study to provide insight into the mode of operation of tDCS on the brain's response to long-term perceptual learning, adding an important piece of evidence from the domain of non-invasive brain stimulation to show that functional changes detectable by fMRI in primary sensory cortices participate in perceptual learning. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.
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    • "We also employed Western blotting to analyze possible alterations in postsynaptic NMDAR expression. Triton X-100-insoluble fraction (TIF) was used to roughly represent the postsynaptic fraction [21]. Different exposure times were selected, and here 1 hr after PT was showed (Figure 2(c), 0 hr after PT, 1.22 ± 0.08, n = 5, *P < 0.05; 1 hr after PT, 1.39 ± 0.07, n = 6, *P < 0.05; 12 hr after PT, 1.05 ± 0.07, n = 5, P > 0.05). "
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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.
    Full-text · Article · Mar 2014 · Neural Plasticity
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    • "In previous studies, we demonstrated that conventional PKC (cPKC)γ membrane translocation is involved in remifentanil-induced hyperalgesia [10]. Moreover, PKC is often consistent with CaMKII in regulating neural plasticity [11–13]. Therefore, in this study, we explored how CaMKII levels change with remifentanil exposure. "
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    ABSTRACT: Background Postoperative remifentanil-induced pain sensitization is common, but its molecular mechanism remains unclear. Calcium/calmodulin-dependent protein kinase II (CaMKII) has been shown to have a critical role in morphine-induced hyperalgesia. This study was designed to determine how CaMKII phosphorylation and protein expression levels change in the central nervous system of rats with remifentanil-induced hyperalgesia. Material/Methods Male Sprague-Dawley® rats were exposed to large-dose (bolus of 6.0 μg/kg and 2.5 μg/kg/min for 2 hours) intravenous remifentanil to induce post-transfusion hyperalgesia. Levels of phosphorylated CaMKII (P-CaMKII) and total protein of CaMKII (T-CaMKII) were determined at different post-transfusion times by Western blot and immunostaining and were compared with controls. Results P-CaMKII increased significantly (P<0.05) at 0, 0.5, and 2 hours. However, P-CaMKII at 5 to 24 hours and T-CaMKII at 0 to 24 hours post-transfusion did not change significantly in rats’ spinal dorsal horn, hippocampus, or primary somatosensory (S1) cortex (n=6 per group). Similarly, immunostaining showed stronger P-CaMKII immunoreactants (P<0.05) and more P-CaMKII- positive cells (P<0.05) in the spinal dorsal horn, CA1 region of the hippocampus, and S1 cortex of rats 0.5 hours post-transfusion compared with the control group treated with 0.9% sodium chloride (n=3 per group). Conclusions These results suggest that a temporary rise in the P-CaMKII level in the central nervous system may correlate with remifentanil-induced pain sensitization in the postoperative period.
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