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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

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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    • "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.
    Neural Plasticity 03/2014; 2014:827161. DOI:10.1155/2014/827161 · 3.60 Impact Factor
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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.
    04/2013; 19(4):118-25. DOI:10.12659/MSMBR.883866
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    • "PKC and MAPK signaling pathways appear to be involved in AMPA receptor trafficking underlying an in vitro model of classical conditioning in pond turtles, Pseudemys scripta elegans (Zheng and Keifer, 2008). PKC activation facilitates autophosphorylated CaMKII and increased association with NMDA receptors in conjunction with NMDA postsynaptic receptor insertion that was, along with PKC-induced LTP of the AMPA receptor-mediated response, abolished by a CaMKII antagonist or by disruption of CaMKII interaction with NR2A or NR2B (Yan et al., 2011). "
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    ABSTRACT: Drug addiction is a severe neuropsychiatric disorder characterized by loss of control over motivated behavior. The need for effective treatments mandates a greater understanding of the causes and identification of new therapeutic targets for drug development. Drugs of abuse subjugate normal reward-related behavior to uncontrollable drug-seeking and -taking. Contributions of brain reward circuitry are being mapped with increasing precision. The role of synaptic plasticity in addiction and underlying molecular mechanisms contributing to the formation of the addicted state are being delineated. Thus we may now consider the role of striatal signal transduction in addiction from a more integrative neurobiological perspective. Drugs of abuse alter dopaminergic and glutamatergic neurotransmission in medium spiny neurons of the striatum. Dopamine receptors important for reward serve as principle targets of drugs abuse, which interact with glutamate receptor signaling critical for reward learning. Complex networks of intracellular signal transduction mechanisms underlying these receptors are strongly stimulated by addictive drugs. Through these mechanisms, repeated drug exposure alters functional and structural neuroplasticity, resulting in transition to the addicted biological state and behavioral outcomes that typify addiction. Ca(2+) and cAMP represent key second messengers that initiate signaling cascades, which regulate synaptic strength and neuronal excitability. Protein phosphorylation and dephosphorylation are fundamental mechanisms underlying synaptic plasticity that are dysregulated by drugs of abuse. Increased understanding of the regulatory mechanisms by which protein kinases and phosphatases exert their effects during normal reward learning and the addiction process may lead to novel targets and pharmacotherapeutics with increased efficacy in promoting abstinence and decreased side effects, such as interference with natural reward, for drug addiction.
    Frontiers in Neuroanatomy 09/2011; 5:60. DOI:10.3389/fnana.2011.00060 · 4.18 Impact Factor
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